U.S. patent application number 17/282297 was filed with the patent office on 2021-10-21 for actuator system.
The applicant listed for this patent is WearOptimo Pty Ltd. Invention is credited to Anthony Mark BREWER, Mark Anthony Fernance KENDALL, Stephen James WILSON.
Application Number | 20210321916 17/282297 |
Document ID | / |
Family ID | 1000005706877 |
Filed Date | 2021-10-21 |
United States Patent
Application |
20210321916 |
Kind Code |
A1 |
KENDALL; Mark Anthony Fernance ;
et al. |
October 21, 2021 |
ACTUATOR SYSTEM
Abstract
A system for performing measurements on a biological subject,
the system including: at least one substrate including a plurality
of microstructures configured to breach a stratum corneum of the
subject; and, an actuator configured to apply a force to the
substrate to cause the microstructures to at least one of pierce
and penetrate the stratum corneum.
Inventors: |
KENDALL; Mark Anthony Fernance;
(Woolloongabba, AU) ; WILSON; Stephen James;
(Woolloongabba, AU) ; BREWER; Anthony Mark;
(Woolloongabba, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
WearOptimo Pty Ltd |
Woolloongabba, Queensland |
|
AU |
|
|
Family ID: |
1000005706877 |
Appl. No.: |
17/282297 |
Filed: |
October 1, 2019 |
PCT Filed: |
October 1, 2019 |
PCT NO: |
PCT/AU2019/051064 |
371 Date: |
April 1, 2021 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/14546 20130101;
A61B 5/6833 20130101; A61B 5/14514 20130101; A61B 5/14735 20130101;
A61B 5/0051 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/00 20060101 A61B005/00; A61B 5/1473 20060101
A61B005/1473 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 2, 2018 |
AU |
2018903714 |
Claims
1) A system for performing measurements on a biological subject,
the system including: a) at least one substrate including a
plurality of microstructures configured to breach a stratum corneum
of the subject; and, b) an actuator configured to apply a force to
the substrate to cause the microstructures to at least one of
pierce and penetrate the stratum corneum.
2) A system according to claim 1, wherein the actuator is at least
one of: a) an electromagnetic actuator; b) a vibratory motor; c) a
piezoelectric actuator; and, d) a mechanical actuator.
3) A system according to claim 1, wherein the actuator is
configured to apply at least one of: a) a vibratory force; b) a
periodic force; c) a repeated force; d) a biasing force; e) a
single continuous force; and, f) a single instantaneous force.
4) A system according to claim 1, wherein the actuator is
configured to apply: a) a vibratory force; and, b) a continuous
biasing force.
5) A system according to claim 1, wherein the actuator includes: a)
an actuator housing including a base having an opening; b) a
biasing member mounted within the actuator housing; and, c) a
mounting coupled to the spring, the mounting being configured to
support a patch including the substrate and microstructures so that
the patch at least partially projects through the opening and
wherein the biasing member applies a biasing force to the mounting
to thereby urge the patch against the stratum corneum.
6) A system according to claim 5, wherein the biasing member is at
least one of: a) a spring; and, b) an electromagnetic actuator.
7) A system according to claim 5, wherein the actuator includes a
vibratory actuator in the mounting and wherein the vibratory
actuator causes the mounting to vibrate, thereby transmitting a
vibratory force to the patch.
8) A system according to claim 7, wherein the vibratory actuator
includes at least one of: a) a vibratory motor; and, b) a
piezoelectric actuator.
9) A system according to claim 1, wherein the force at least one
of: a) includes a biasing force that is at least one of: i) greater
than 0.1 N; ii) greater than 1 N; iii) less than 50 N; iv) less
than 10 N; and, v) about 2.5 to 5 N; and, b) includes a vibratory
force that is at least one of: i) at least 1 mN; ii) about 200 mN;
and, iii) less than 1000 mN; and, c) is applied at a frequency that
is at least one of: i) at least 10 Hz; ii) about 100 to 200 Hz;
and, iii) less than 1 kHz.
10) A system according to claim 9, wherein the vibratory force is
applied at a frequency that is at least one of: a) varying; b)
varying depending on at least one of: i) a time of application; ii)
a depth of penetration; iii) a degree of penetration; and, iv) an
insertion resistance; and, c) increasing with an increasing depth
of penetration; d) decreasing with an increasing depth of
penetration; e) increasing until a point of penetration; and f)
decreasing after a point of penetration.
11) A system according to claim 1, wherein the force is at least
one of: a) varying depending on at least one of: i) a time of
application; ii) a depth of penetration; iii) a degree of
penetration; and, iv) an insertion resistance; b) increasing with
an increasing depth of penetration; c) decreasing with an
increasing depth of penetration; d) increasing until a point of
penetration; and e) decreasing after a point of penetration.
12) A system according to claim 1, wherein the actuator is
configured to cause movement of the microstructures that is at
least one of: a) greater than 0.001 times a length of the
microstructure; b) greater than 0.01 times a length of the
microstructure; c) greater than 0.1 times a length of the
microstructure; d) greater than a length of the microstructure; e)
greater than 10 times a length of the microstructure; f) greater
than 100 times a length of the microstructure; and, g) greater than
1000 times a length of the microstructure. h) varying depending on
at least one of: i) a time of application; ii) a depth of
penetration; iii) a degree of penetration; and, iv) an insertion
resistance; i) increasing with an increasing depth of penetration;
j) decreasing with an increasing depth of penetration; k)
increasing until a point of penetration; and l) decreasing after a
point of penetration.
13) A system according to claim 1 wherein the system: a) detects,
using response of the actuator, at least one of: i) a depth of
penetration; ii) a degree of penetration; and, iii) an insertion
resistance; b) controls the actuator in accordance with the
detection.
14) A system according to claim 1, wherein the system: a) detects,
using measured response signals, at least one of: i) breaching of
the barrier by the microstructures; and, ii) a depth of penetration
by the microstructures; b) controls the actuator in accordance with
the detection.
15) A system according to claim 1, wherein the actuator is
configured to at least one of: a) physically disrupt a coating on
the microstructures; b) dislodge a coating on the microstructures;
c) physically stimulate the subject; d) cause the microstructures
to penetrate the barrier; e) retract the microstructures from the
barrier; and, f) retract the microstructures from the subject.
16) A system according to claim 1, wherein the system includes a
housing that at least one of: a) contains the actuator; and, b)
acts as the actuator.
17) A system according to claim 16, wherein the housing selectively
couples to the substrate.
18) A system according to claim 17, wherein the housing couples to
the substrate using at least one of: a) mechanical coupling; b)
adhesive coupling; and, c) magnetic coupling.
19) A system according to claim 16, wherein the housing includes
housing connectors that operatively connect to substrate connectors
on the substrate to allow signals to be applied to and/or received
from the microstructures.
20) A system according to claim 1, wherein at least one of a
housing and substrate are at least one of: a) secured to the
subject; b) secured to the subject using anchor microstructures; c)
secured to the subject using an adhesive patch; and, d) secured to
the subject using a strap.
21) A system according to claim 1, wherein the actuator is
operatively coupled to the substrate.
22) A system according to claim 1, wherein the system includes at
least one of: a) at least one sensor operatively connected to at
least one microstructure, the at least one sensor being configured
to measure response signals from the at least one microstructure;
and, b) a signal generator operatively connected to at least one
microstructure to apply a stimulatory signal to the at least one
microstructure.
23) A system according to claim 1, wherein the system includes one
or more electronic processing devices configured to at least one
of: a) control the actuator; b) determine measured response
signals; and, c) control a signal generator.
24) A system according to claim 1, wherein the system includes one
or more electronic processing devices that control the
actuator.
25) A system according to claim 1, wherein the actuator is
configured to at least one of: a) physically disrupt a coating on
the microstructures; b) dislodge a coating on the microstructures;
c) physically stimulate the subject; d) cause the microstructures
to penetrate the barrier; e) retract the microstructures from the
barrier; and, f) retract the microstructures from the subject.
26) A system according to claim 1, wherein at least one of the
substrate and the microstructures include at least one of: a)
metal; b) polymer; and, c) silicon.
27) A system according to claim 1, wherein the substrate is at
least one of: a) at least partially flexible; b) configured to
conform to an outer surface of the functional barrier; and, c)
configured to conform to a shape of at least part of a subject.
28) A system according to claim 1, wherein at least some of the
microstructures are plate microstructures at least partially
tapered and having a substantially rounded rectangular cross
sectional shape.
29) A system according to claim 1, wherein the microstructures
include anchor microstructures used to anchor the substrate to the
subject and wherein the anchor microstructures at least one of: a)
undergo a shape change; b) undergo a shape change in response to at
least one of substances in the subject and applied stimulation; c)
swell; d) swell in response to at least one of substances in the
subject and applied stimulation; e) include anchoring structures;
f) have a length greater than that of other microstructures; g) are
rougher than other microstructures; h) have a higher surface
friction than other microstructures; i) are blunter than other
microstructures; j) are fatter than other microstructures; and, k)
enter the dermis.
30) A system according to claim 1, wherein at least some of the
microstructures have at least one of: a) a length that is at least
one of: i) less than 2500 .mu.m; ii) less than 1000 .mu.m; iii)
less than 750 .mu.m; iv) less than 450 .mu.m; v) less than 300
.mu.m; vi) less than 250 .mu.m; vii) about 250 .mu.m; viii) about
150 .mu.m; ix) greater than 100 .mu.m; x) greater than 50 .mu.m;
and, xi) greater than 10 .mu.m; b) a maximum width that is at least
one of: i) less than 2500 .mu.m; ii) less than 1000 .mu.m; iii)
less than 750 .mu.m; iv) less than 450 .mu.m; v) less than 300
.mu.m; vi) less than 250 .mu.m; vii) of a similar order of
magnitude to the length; viii) greater than the length; ix) greater
than the length; x) about the same as the length; xi) about 250
.mu.m; xii) about 150 .mu.m; and, xiii) greater than 50 .mu.m; and,
c) a maximum thickness that is at least one of: i) less that the
width; ii) significantly less that the width; iii) of a smaller
order of magnitude to the length; iv) less than 300 .mu.m; v) less
than 200 .mu.m; vi) less than 50 .mu.m; vii) about 25 .mu.m; and,
viii) greater than 10 .mu.m.
31) A system according to claim 1, wherein at least some of the
microstructures include at least one of: a) a shoulder that is
configured to abut against the stratum corneum to control a depth
of penetration; and, b) a shaft extending from a shoulder to the
tip, the shaft being configured to control a position of the tip in
the subject.
32) A system according to claim 1, wherein the microstructures have
at least one of: a) a density that is at least one of: i) less than
5000 per cm.sup.2; ii) greater than 100 per cm.sup.2; and, iii)
about 600 per cm.sup.2; and, b) a spacing that is at least one of:
i) less than 1 mm; ii) about 0.5 mm; iii) about 0.2 mm; iv) about
0.1 mm; and, v) more than 10 .mu.m.
33) A system according to claim 1, wherein at least some of the
microstructures are arranged in groups, and wherein at least one
of: a) response signals are measured between microstructures in a
group; and, b) stimulation is applied between microstructures in a
group.
34) A system according to claim 33, wherein the group is a pair of
microstructures including spaced apart plate microstructures having
substantially planar electrodes in opposition.
35) A system according to claim 34, wherein at least one of: a) at
least some pairs of microstructures are angularly offset; b) at
least some pairs of microstructures are orthogonally arranged; c)
adjacent pairs of microstructures are orthogonally arranged; d)
pairs of microstructures are arranged in rows, and the pairs of
microstructures in one row are angularly offset relative to pairs
of microstructures in other rows; e) pairs of microstructures are
arranged in rows, and the pairs of microstructures in one row are
orthogonally arranged relative to pairs of microstructures in other
rows.
36) A system arrangement according to claim 33, wherein at least
one of: a) the spacing between the electrodes in each group are at
least one of: i) less than 10 mm; ii) less than 1 mm; iii) about
0.1 mm; and, iv) more than 10 .mu.m; and, b) a spacing between
groups of microstructures is at least one of: i) less than 50 mm;
ii) more than 20 mm; iii) less than 20 mm; iv) less than 10 mm; v)
more than 10 mm; vi) less than 1 mm; vii) more than 1 mm; viii)
about 0.5 mm; and, ix) more than 0.2 mm.
37) A system according to claim 1, wherein the microstructures
include a material including at least one of: a) a bioactive
material; b) a reagent for reacting with analytes in the subject;
c) a binding agent for binding with analytes of interest; d) a
material for binding one or more analytes of interest; e) a probe
for selectively targeting analytes of interest; f) a material to
reduce biofouling; g) a material to attract at least one substance
to the microstructures; h) a material to repel at least one
substance from the microstructures; i) a material to attract at
least some analytes to the projections; and, j) a material to repel
at least some analytes from the projections.
38) A system according to claim 1, wherein the substrate includes a
plurality of microstructures and wherein different microstructures
are at least one of: a) differentially responsive to analytes; b)
responsive to different analytes; c) responsive to different
combination of analytes; and, d) responsive to different levels or
concentrations of analytes.
39) A system according to claim 1, wherein at least some of the
microstructures at least one of: a) attracts at least one substance
to the microstructures; b) repels at least one substance from the
microstructures; c) attracts at least one analyte to the
microstructures; and, d) repels at least one analyte from the
microstructures.
40) A system according to claim 1, wherein the one or more
microstructure electrodes interact with one or more analytes of
interest such that a response signal is dependent on a presence,
absence, level or concentration of analytes of interest.
41) A system according to claim 1, wherein at least some of the
microstructures are coated with a coating.
42) A system according to claim 41, wherein at least one of: a) at
least some microstructures are uncoated; b) at least some
microstructures are porous with an internal coating; c) at least
some microstructures are partially coated; d) different
microstructures have different coatings; e) different parts of
microstructures include different coatings; and, f) at least some
microstructures include multiple coatings.
43) A system according to claim 41, wherein stimulation is used to
at least one of: a) release material from the coating on the
microstructure; b) disrupt the coating; c) dissolve the coating;
and, d) release the coating.
44) A system according to claim 41, wherein at least some of the
microstructures are coated with a selectively dissolvable
coating.
45) A system according to claim 41, wherein the coating at least
one of: a) interacts with analytes; b) undergoes a shape change to
selectively anchor microstructures; c) modifies surface properties
to at least one of: i) increase hydrophilicity; ii) increase
hydrophobicity; iii) minimize biofouling; d) attracts at least one
substance to the microstructures; e) repels at least one substance
from the microstructures; f) provides a physical structure to at
least one of: i) facilitate penetration of the barrier; ii)
strengthen the microstructures; and, iii) anchor the
microstructures in the subject; g) dissolves to at least one of: i)
expose a microstructure; ii) expose a further coating; and, iii)
expose a material; h) provides stimulation to the subject; i)
contains a material; and, j) selectively releases a material; k)
acts as a barrier to preclude at least one substance from the
microstructures; and, l) includes at least one of: i) polyethylene;
ii) polyethylene glycol; iii) polyethylene oxide; iv) zwitterions;
v) peptides; vi) hydrogels; and, vii) self-assembled monolayer.
46) A system according to claim 1, wherein the microstructures are
configured to deliver stimulation to trigger a biological response
in the subject.
47) A system according to claim 1, wherein the system is configured
to perform repeated measurements over a time period.
48) A system according to claim 47, wherein the time period is at
least one of: a) at least one minute; b) at least one hour; c) at
least one day; and, d) at least one week.
49) A system according to claim 47, wherein the microstructures are
configured to remain in the subject during the time period.
50) A system according to claim 47, wherein the microstructures are
configured to be removed when measurements are not being
performed.
51) A system according to claim 1, wherein the actuator is
configured to apply a force to the substrate to at least one of: a)
sense tissue mechanical properties; b) provide mechanical
stimulation; c) attract or repel substances; d) trigger a
biological response; e) release material from a coating on at least
some microstructures; f) disrupt a coating on at least some
microstructures; g) dissolve a coating on at least some
microstructures; h) dislodge a coating on the microstructures; i)
release a coating on at least some microstructures. j) cause the
microstructures to penetrate the barrier; k) retract the
microstructures from the barrier; and, l) retract the
microstructures from the subject.
52) A system according to claim 1, wherein the system includes a
monitoring device and a patch including the substrate and
microstructures.
53) A system according to claim 52, wherein the monitoring device
includes the actuator.
54) A system according to claim 1, wherein the system is at least
partially wearable.
55) A method for performing measurements on a biological subject,
the method including: a) using at least one substrate including a
plurality of microstructures configured to breach a stratum corneum
of the subject; and, using an actuator configured to apply a force
to the substrate to cause the microstructures to at least one of
pierce and penetrate the stratum corneum.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to an actuator system and
method for use with a system for performing measurements on a
biological subject, and in one particular example, to an actuator
system for causing breaching of a functional barrier of the subject
using microstructures.
DESCRIPTION OF THE PRIOR ART
[0002] The reference in this specification to any prior publication
(or information derived from it), or to any matter which is known,
is not, and should not be taken as an acknowledgment or admission
or any form of suggestion that the prior publication (or
information derived from it) or known matter forms part of the
common general knowledge in the field of endeavour to which this
specification relates.
[0003] Biological markers, such as proteins, antibodies, cells,
small chemicals, hormones and nucleic acids, whose presence in
excess or deficiency may indicate a diseased state, have been found
in blood serum and their levels are routinely measured for research
and for clinical diagnosis. Standard tests include antibody
analysis for detecting infections, allergic responses, and
blood-borne cancer markers (e.g. prostate specific antigen analysis
for detecting prostate cancer). The biological markers may
originate from many organ systems in the body but are extracted
from a single compartment, the venous blood.
[0004] However, this is not suitable for all conditions as often
blood does not contain key biological markers for diseases
originating in solid tissues, and whilst this problem has been
partially overcome by taking tissue biopsies, this is
time-consuming, painful, risky, costly and can require
highly-skilled personnel such as surgeons.
[0005] Another serum-rich fluid is the interstitial fluid (ISF)
which fills the intercellular spaces in solid tissues and
facilitates the passage of nutrients, biomarkers, and excretory
products via the blood stream.
[0006] WO2005/072630 describes devices for delivering bioactive
materials and other stimuli to living cells, methods of manufacture
of the device and various uses of the device, including a number of
medical applications. The device comprises a plurality of
structures which can penetrate a body surface so as to deliver the
bioactive material or stimulus to the required site. The structures
are typically solid and the delivery end section of the structure
is so dimensioned as to be capable of insertion into targeted cells
to deliver the bioactive material or stimulus without appreciable
damage to the targeted cells or specific sites therein.
[0007] The use of microneedle versions of such arrays in sampling
fluids is also known. However, the techniques focus on the use of
micro-fluidic techniques such as capillary or pumping actions to
extract fluid, as described for example in U.S. Pat. Nos.
6,923,764, 6,052,652, 6,591,124, 6,558,361, 6,908,453, and
US2005/0261632, US2006/0264782, US2005/0261632, US2005/0261632,
U.S. Pat. No. 6,589,202.
[0008] However, these systems suffer from a number of drawbacks.
Firstly, use of capillary or pumping actions can only be achieved
using relatively largely structures, which typically pass through
the dermis and consequently can end up sampling blood as opposed to
interstitial fluid. This can also cause discomfort and irritation
to the subject being sampled. Secondly, the requirement for
capillary or pumping actions renders the arrays complex, in
structure and requiring power sources resulting in arrays that are
difficult and expensive to manufacture, liable to infection, making
them unsuitable for general use.
[0009] Other in vitro diagnostic devices are known, such as the use
of arrays that include silicon nanowires, or other complex
detection mechanisms, such as direct radio-frequency detection of
nucleotide hybridization to perform the detection. Again, the
fabrication of such systems is complex and expensive, again making
these unsuitable for practical applications.
[0010] U.S. Pat. No. 9,974,471 describes a device and system for
measuring and/or monitoring an analyte present on the skin is
provided. The system includes a skin-mountable device that may be
attached to an external skin surface and a reader device. The
skin-mountable device includes a substrate, a plurality of
microneedles, and nanosensors. The microneedles are attached to the
substrate such that attachment of the substrate to an external skin
surface causes to the microneedles to penetrate into the epidermis,
intradermis, or dermis. The nanosensors include a detectable label
and are configured to interact with a target analyte present in the
interstitial fluid in the epidermis, intradermis, or dermis. The
reader device is configured to detect the analyte in interstitial
fluid via interaction with the skin-mountable device.
[0011] US20070142885 describes a system and method for revitalizing
aging skin using electromagnetic energy that is delivered using a
plurality of needles that are capable of penetrating the skin to
desired depths. A particular aspect of the invention is the
capability to spare zones of tissue from thermal exposure. This
sparing of tissue allows new tissue to be regenerated while the
heat treatment can shrink the collagen and tighten the underlying
structures. Additionally, the system is capable of delivering
therapeutically beneficial substances either through the
penetrating needles or through channels that have been created by
the penetration of the needles.
[0012] U.S. Pat. No. 6,972,013 describes methods for using an
electric field to delivery therapeutic or immunizing treatment to a
subject by applying non-invasive, user-friendly electrodes to the
surface of the skin. Thus, therapeutic or immunizing agents can be
delivered into cells of skin for local and systemic treatments or
for immunization with optimal gene expression and minimal tissue
damage. In particular, therapeutic agents include naked or
formulated nucleic acid, polypeptides and chemotherapeutic
agents.
[0013] U.S. Pat. No. 7,285,090 describes a monitoring apparatus
that includes a sensor device and an I/O device in communication
with the sensor device that generates derived data using the data
from the sensor device. The derived data cannot be directly
detected by the associated sensors. Alternatively, an apparatus
that includes a wearable sensor device and an I/O device in
communication with the sensor device that includes means for
displaying information and a dial for entering information.
Alternatively, an apparatus for tracking caloric consumption and
caloric expenditure data that includes a sensor device and an I/O
device in communication with the sensor device. The sensor device
includes a processor programmed to generate data relating to
caloric expenditure from sensor data. Alternatively, an apparatus
for tracking caloric information for an individual that utilizes a
plurality of classification identifiers for classifying meals
consumed by the individual, each of the classification identifiers
having a corresponding caloric amount.
[0014] US20110295100 describes methods, systems and/or devices for
enhancing conductivity of an electrical signal through a subject's
skin using one or more microneedle electrodes are provided. A
microneedle electrode may be applied to the subject's skin by
placing the microneedle electrode in direct contact with the
subject's skin. The microneedles of the microneedle electrode may
be inserted into the skin such that the microneedles pierce stratum
corneum of the skin up to or through dermis of the skin. An
electrical signal passes or is conducted through or across the
microneedle electrode and the subject's skin, where impedance of
the microneedle electrode is minimal and greatly reduced compared
to existing technologies.
[0015] WO2009140735 describes an apparatus for use in detecting
analytes in a subject, wherein the apparatus includes a number of
structures provided on a patch, such that applying the patch to the
subject causes at least some of the structures to be inserted into
the subject and target one or more analytes and a reagent for
detecting the presence or absence of analytes.
[0016] U.S. Pat. No. 10,098,574 describes device and system for
measuring and/or monitoring an analyte present on the skin is
provided. The system includes a skin-mountable device that may be
attached to an external skin surface and a reader device. The
skin-mountable device includes a substrate, a plurality of
micro-needles, and nanosensors encapsulated in the micro-needles.
The micro-needles are attached to the substrate such that
attachment of the substrate to an external skin surface causes to
the micro-needles to penetrate into the skin to contact
interstitial fluid. The micro-needles can include a sacrificial
agent and are configured to become porous on contact with a
solvent, e.g., interstitial fluid, which dissolves at least a
portion of the sacrificial agent. The nanosensors encapsulated in
the micro-needles include a detectable label and are configured to
interact with a target analyte present in the interstitial fluid.
The reader device is configured to detect the analyte in
interstitial fluid via interaction with the skin-mountable
device.
[0017] US 2016/0256091 describes a bio information measuring device
is provided. The bio information measuring device includes a sensor
portion and a needle portion including a plurality of needles
projecting from a plurality of openings formed in a surface of the
sensor portion. The plurality of needles are configured to pierce
tissue, wherein the plurality of needles include a biocompatible
organic material which includes an enzyme member that reacts with
an analysis material and a conductive polymer for transferring an
electrical signal generated as a result of a reaction of the enzyme
member with the analysis material.
[0018] US 2018/0177439 describes at least one microneedle comprises
a hydrogel material that includes a substance that fluoresces when
the substance interacts with an analyte. A magnitude of the
fluorescence varies as a function of the concentration of the
analyte. During use, the hydrogel material is illuminated with
illumination light in a first wavelength range while the hydrogel
material interfaces with the dermal interstitial fluid layer of a
subject, and a photosensor generates an output that corresponds to
an amount of light received in a second wavelength range.
[0019] US 2007/0276211 describes a biomedical monitor is disclosed.
The biomedical monitor has an array of moveable microneedles coated
with a first chemical sensing media. The biomedical monitor also
has an actuator configured to move at least one microneedle in the
array of microneedles from a retracted position to an engaged
position whereby the at least one microneedle enters a subject's
skin. The biomedical monitor further has an optical system
configured to illuminate the at least one microneedle during or
after entering the subject's skin and monitor the first chemical
sensing media from the at least one microneedle, whereby at least
one biomedical characteristic is determined based on at least one
spectral property of the monitored first chemical sensing media. A
method of monitoring at least one biomedical characteristic is also
disclosed.
[0020] WO2013058879A2 describes methods, structures, and systems
are disclosed for biosensing and drug delivery techniques. In one
aspect, a device for detecting an analyte and/or releasing a
biochemical into a biological fluid can include an array of
hollowed needles, in which each needle includes a protruded needle
structure including an exterior wall forming a hollow interior and
an opening at a terminal end of the protruded needle structure that
exposes the hollow interior, and a probe inside the exterior wall
to interact with one or more chemical or biological substances that
come in contact with the probe via the opening to produce a probe
sensing signal, and an array of wires that are coupled to probes of
the array of hollowed needles, respectively, each wire being
electrically conductive to transmit the probe sensing signal
produced by a respective probe.
[0021] US20150208984 describes a transdermal microneedle continuous
monitoring system. The continuous system monitoring includes a
substrate, a microneedle unit, a signal processing unit and a power
supply unit. The microneedle unit at least comprises a first
microneedle set used as a working electrode and a second
microneedle set used as a reference electrode, the first and second
microneedle sets arranging on the substrate. Each microneedle set
comprises at least a microneedle. The first microneedle set
comprises at least a sheet having a through hole on which a barbule
forms at the edge. One of the sheets provides the through hole from
which the barbules at the edge of the other sheets go through, and
the barbules are disposed separately.
[0022] US 2016/0302687 describes a biometric information measuring
sensor is provided that includes a base comprising a plurality of
bio-marker measuring areas and a plurality of electrodes. Each of
the plurality of electrodes is disposed on a respective one of the
plurality of bio-marker measuring areas, and each of the plurality
of electrodes includes a working electrode and a counter electrode
spaced apart from the working electrode. The biometric information
measuring sensor also includes a plurality of needles. Each of the
needles is disposed on a respective one of the plurality of
electrodes. Two or more of the plurality of needles have different
lengths.
[0023] US 2016/0166184 describes a microneedle device (200)
including at least one microneedle (1) having one or more nanowires
(203) on a surface of said at least one microneedle. The
microneedle device is typically used in a sensor such as a sensor
for monitoring glucose levels in the body and the nanowires may
have a membrane (207) covering at least part of the nanowires.
[0024] KR 20170041375 describes a micro-needle skin patch
functionalized with early diagnosis aptamer coated carbon nanotubes
of various diseases.
[0025] U.S. Pat. No. 8,543,179 describes a biomedical sensor device
includes a light source, a probe array, and a photo detector. The
light source is configured for emitting infrared radiation. The
probe array is contacted to a user's skin to detect an electric
wave signal transmitted through the probe array from the skin. The
probe array includes a substrate and a plurality of probes mounted
on the substrate, wherein the substrate and the probes are
non-opaque so that the infrared radiation may be transmitted
through the probe array into the skin. The photo detector is
configured to detect an infrared signal by measuring the infrared
radiation absorption by the skin.
[0026] U.S. Pat. No. 8,588,884 describes devices for enhancing
conductivity of an electrical signal through a subject's skin using
one or more microneedle electrodes are provided. A microneedle
electrode may be applied to the subject's skin by placing the
microneedle electrode in direct contact with the subject's skin.
The microneedles of the microneedle electrode may be inserted into
the skin such that the microneedles pierce stratum corneum of the
skin up to or through dermis of the skin. An electrical signal
passes or is conducted through or across the microneedle electrode
and the subject's skin, where impedance of the microneedle
electrode is minimal and greatly reduced compared to existing
technologies.
[0027] US 2016/0051195 describes skin-conformal sensor devices and
methods of using the same. As consistent with one or more
embodiments, a sensor device includes an upper portion and lower
portion. The upper portion includes a plurality of layers including
at least one sensor. The lower portion includes a layer of
microstructures configured and arranged to interface with skin of a
subject and to interlock the skin with the at least one sensor.
[0028] US 2005/0261606 describes a device for sampling at least one
biological fluid constituent and measuring at least one target
constituent within the biological fluid. The device has at least
one micro-needle having an open distal end used to penetrate the
skin to a depth where pain and bleeding are minimized. The device
further includes a hydrophilic gel within the micro-needle for
sampling the biological fluid constituents and an electrochemical
cell for measuring the concentration of targeted constituents
within the sampled biological fluid constituents. In certain
embodiments, the electrochemical cell is integrated within the
micro-needle whereby the steps of sampling and measuring are
performed completely in-situ. In other embodiments, the
electrochemical cell is located external to the micro-needle at its
proximal end. Constituent sampling and measurement systems, methods
and kits are also provided.
[0029] WO 2018/124327 describes a method for fabricating an
aptamer-coated, microneedle-based diagnostic skin patch and a patch
fabricated thereby. The patch has the advantage of attaching a
great number of aptamers, which are much smaller in size than
antibodies, onto a relatively great number of microneedle tip
surfaces. Allowing the attachment of aptamers for various kinds of
biomarkers all together thereto, the patch can also simultaneously
detect various kinds of materials (multiplexing). Therefore, a
microneedle tip-based skin patch can also be used as a protein chip
using an aptamer.
SUMMARY OF THE PRESENT INVENTION
[0030] In one broad form an aspect of the present invention seeks
to provide a system for performing measurements on a biological
subject, the system including: at least one substrate including a
plurality of microstructures configured to breach a stratum corneum
of the subject; and, an actuator configured to apply a force to the
substrate to cause the microstructures to at least one of pierce
and penetrate the stratum corneum.
[0031] In one broad form an aspect of the present invention seeks
to provide a method for performing measurements on a biological
subject, the method including: using at least one substrate
including a plurality of microstructures configured to breach a
stratum corneum of the subject; and, using an actuator configured
to apply a force to the substrate to cause the microstructures to
at least one of pierce and penetrate the stratum corneum.
[0032] In one embodiment the actuator is at least one of: an
electromagnetic actuator; a vibratory motor; a piezoelectric
actuator; and, a mechanical actuator.
[0033] In one embodiment the actuator is configured to apply at
least one of: a vibratory force; a periodic force; a repeated
force; a biasing force; a single continuous force; and, a single
instantaneous force.
[0034] In one embodiment the actuator is configured to apply: a
vibratory force; and, a continuous biasing force.
[0035] In one embodiment the actuator includes: an actuator housing
including a base having an opening; a biasing member mounted within
the actuator housing; and, a mounting coupled to the spring, the
mounting being configured to support a patch including the
substrate and microstructures so that the patch at least partially
projects through the opening and wherein the biasing member applies
a biasing force to the mounting to thereby urge the patch against
the stratum corneum.
[0036] In one embodiment the biasing member is at least one of: a
spring; and, an electromagnetic actuator.
[0037] In one embodiment the actuator includes a vibratory actuator
in the mounting and wherein the vibratory actuator causes the
mounting to vibrate, thereby transmitting a vibratory force to the
patch.
[0038] In one embodiment the vibratory actuator includes at least
one of: a vibratory motor; and, a piezoelectric actuator.
[0039] In one embodiment the force at least one of: includes a
biasing force that is at least one of: greater than 0.1 N; greater
than 1 N; less than 50 N; less than 10 N; and, about 2.5 to 5 N;
and, includes a vibratory force that is at least one of: at least 1
mN; about 200 mN; and, less than 1000 mN; and, is applied at a
frequency that is at least one of: at least 10 Hz; about 100 to 200
Hz; and, less than 1 kHz.
[0040] In one embodiment the vibratory force is applied at a
frequency that is at least one of: varying; varying depending on at
least one of: a time of application; a depth of penetration; a
degree of penetration; and, an insertion resistance; and,
increasing with an increasing depth of penetration; decreasing with
an increasing depth of penetration; increasing until a point of
penetration; and decreasing after a point of penetration.
[0041] In one embodiment the force is at least one of: varying
depending on at least one of: a time of application; a depth of
penetration; a degree of penetration; and, an insertion resistance;
increasing with an increasing depth of penetration; decreasing with
an increasing depth of penetration; increasing until a point of
penetration; and decreasing after a point of penetration.
[0042] In one embodiment the actuator is configured to cause
movement of the microstructures that is at least one of: greater
than 0.001 times a length of the microstructure; greater than 0.01
times a length of the microstructure; greater than 0.1 times a
length of the microstructure; greater than a length of the
microstructure; greater than 10 times a length of the
microstructure; greater than 100 times a length of the
microstructure; and, greater than 1000 times a length of the
microstructure. varying depending on at least one of: a time of
application; a depth of penetration; a degree of penetration; and,
an insertion resistance; increasing with an increasing depth of
penetration; decreasing with an increasing depth of penetration;
increasing until a point of penetration; and decreasing after a
point of penetration.
[0043] In one embodiment the system: detects, using response of the
actuator, at least one of: a depth of penetration; a degree of
penetration; and, an insertion resistance; controls the actuator in
accordance with the detection.
[0044] In one embodiment the system: detects, using measured
response signals, at least one of: breaching of the barrier by the
microstructures; and, a depth of penetration by the
microstructures; controls the actuator in accordance with the
detection.
[0045] In one embodiment the actuator is configured to at least one
of: physically disrupt a coating on the microstructures; dislodge a
coating on the microstructures; physically stimulate the subject;
cause the microstructures to penetrate the barrier; retract the
microstructures from the barrier; and, retract the microstructures
from the subject.
[0046] In one embodiment the system includes a housing that at
least one of: contains the actuator; and, acts as the actuator.
[0047] In one embodiment the housing selectively couples to the
substrate.
[0048] In one embodiment the housing couples to the substrate using
at least one of: mechanical coupling; adhesive coupling; and,
magnetic coupling.
[0049] In one embodiment the housing includes housing connectors
that operatively connect to substrate connectors on the substrate
to allow signals to be applied to and/or received from the
microstructures.
[0050] In one embodiment at least one of a housing and substrate
are at least one of: secured to the subject; secured to the subject
using anchor microstructures; secured to the subject using an
adhesive patch; and, secured to the subject using a strap.
[0051] In one embodiment the actuator is operatively coupled to the
substrate.
[0052] In one embodiment the system includes at least one of: at
least one sensor operatively connected to at least one
microstructure, the at least one sensor being configured to measure
response signals from the at least one microstructure; and, a
signal generator operatively connected to at least one
microstructure to apply a stimulatory signal to the at least one
microstructure.
[0053] In one embodiment the system includes one or more electronic
processing devices configured to at least one of: control the
actuator; determine measured response signals; and, control a
signal generator.
[0054] In one embodiment the system includes one or more electronic
processing devices that control the actuator.
[0055] In one embodiment the actuator is configured to at least one
of: physically disrupt a coating on the microstructures; dislodge a
coating on the microstructures; physically stimulate the subject;
cause the microstructures to penetrate the barrier; retract the
microstructures from the barrier; and, retract the microstructures
from the subject.
[0056] In one embodiment at least one of the substrate and the
microstructures include at least one of: metal; polymer; and,
silicon.
[0057] In one embodiment the substrate is at least one of: at least
partially flexible; configured to conform to an outer surface of
the functional barrier; and, configured to conform to a shape of at
least part of a subject.
[0058] In one embodiment at least some of the microstructures are
plate microstructures at least partially tapered and having a
substantially rounded rectangular cross sectional shape.
[0059] In one embodiment the microstructures include anchor
microstructures used to anchor the substrate to the subject and
wherein the anchor microstructures at least one of: undergo a shape
change; undergo a shape change in response to at least one of
substances in the subject and applied stimulation; swell; swell in
response to at least one of substances in the subject and applied
stimulation; include anchoring structures; have a length greater
than that of other microstructures; are rougher than other
microstructures; have a higher surface friction than other
microstructures; are blunter than other microstructures; are fatter
than other microstructures; and, enter the dermis.
[0060] In one embodiment at least some of the microstructures have
at least one of: a length that is at least one of: less than 2500
.mu.m; less than 1000 .mu.m; less than 750 .mu.m; less than 450
.mu.m; less than 300 .mu.m; less than 250 .mu.m; about 250 .mu.m;
about 150 .mu.m; greater than 100 .mu.m; greater than 50 .mu.m;
and, greater than 10 .mu.m; a maximum width that is at least one
of: less than 2500 .mu.m; less than 1000 .mu.m; less than 750
.mu.m; less than 450 .mu.m; less than 300 .mu.m; less than 250
.mu.m; of a similar order of magnitude to the length; greater than
the length; greater than the length; about the same as the length;
about 250 .mu.m; about 150 .mu.m; and, greater than 50 .mu.m; and,
a maximum thickness that is at least one of: less that the width;
significantly less that the width; of a smaller order of magnitude
to the length; less than 300 .mu.m; less than 200 .mu.m; less than
50 .mu.m; about 25 .mu.m; and, greater than 10 .mu.m.
[0061] In one embodiment at least some of the microstructures
include at least one of: a shoulder that is configured to abut
against the stratum corneum to control a depth of penetration; and,
a shaft extending from a shoulder to the tip, the shaft being
configured to control a position of the tip in the subject.
[0062] In one embodiment the microstructures have at least one of:
a density that is at least one of: less than 5000 per cm.sup.2;
greater than 100 per cm.sup.2; and, about 600 per cm.sup.2; and, a
spacing that is at least one of: less than 1 mm; about 0.5 mm;
about 0.2 mm; about 0.1 mm; and, more than 10 .mu.m.
[0063] In one embodiment at least some of the microstructures are
arranged in groups, and wherein at least one of: response signals
are measured between microstructures in a group; and, stimulation
is applied between microstructures in a group.
[0064] In one embodiment the group is a pair of microstructures
including spaced apart plate microstructures having substantially
planar electrodes in opposition.
[0065] In one embodiment at least one of: at least some pairs of
microstructures are angularly offset; at least some pairs of
microstructures are orthogonally arranged; adjacent pairs of
microstructures are orthogonally arranged; pairs of microstructures
are arranged in rows, and the pairs of microstructures in one row
are angularly offset relative to pairs of microstructures in other
rows; pairs of microstructures are arranged in rows, and the pairs
of microstructures in one row are orthogonally arranged relative to
pairs of microstructures in other rows.
[0066] In one embodiment at least one of: the spacing between the
electrodes in each group are at least one of: less than 10 mm; less
than 1 mm; about 0.1 mm; and, more than 10 .mu.m; and, a spacing
between groups of microstructures is at least one of: less than 50
mm; more than 20 mm; less than 20 mm; less than 10 mm; more than 10
mm; less than 1 mm; more than 1 mm; about 0.5 mm; and, more than
0.2 mm.
[0067] In one embodiment the microstructures include a material
including at least one of: a bioactive material; a reagent for
reacting with analytes in the subject; a binding agent for binding
with analytes of interest; a material for binding one or more
analytes of interest; a probe for selectively targeting analytes of
interest; a material to reduce biofouling; a material to attract at
least one substance to the microstructures; a material to repel at
least one substance from the microstructures; a material to attract
at least some analytes to the projections; and, a material to repel
at least some analytes from the projections.
[0068] In one embodiment the substrate includes a plurality of
microstructures and wherein different microstructures are at least
one of: differentially responsive to analytes; responsive to
different analytes; responsive to different combination of
analytes; and, responsive to different levels or concentrations of
analytes.
[0069] In one embodiment at least some of the microstructures at
least one of: attracts at least one substance to the
microstructures; repels at least one substance from the
microstructures; attracts at least one analyte to the
microstructures; and, repels at least one analyte from the
microstructures.
[0070] In one embodiment the one or more microstructure electrodes
interact with one or more analytes of interest such that a response
signal is dependent on a presence, absence, level or concentration
of analytes of interest.
[0071] In one embodiment at least some of the microstructures are
coated with a coating.
[0072] In one embodiment at least one of: at least some
microstructures are uncoated; at least some microstructures are
porous with an internal coating; at least some microstructures are
partially coated; different microstructures have different
coatings; different parts of microstructures include different
coatings; and, at least some microstructures include multiple
coatings.
[0073] In one embodiment stimulation is used to at least one of:
release material from the coating on the microstructure; disrupt
the coating; dissolve the coating; and, release the coating.
[0074] In one embodiment at least some of the microstructures are
coated with a selectively dissolvable coating.
[0075] In one embodiment the coating at least one of: interacts
with analytes; undergoes a shape change to selectively anchor
microstructures; modifies surface properties to at least one of:
increase hydrophilicity; increase hydrophobicity; minimize
biofouling; attracts at least one substance to the microstructures;
repels at least one substance from the microstructures; provides a
physical structure to at least one of: facilitate penetration of
the barrier; strengthen the microstructures; and, anchor the
microstructures in the subject; dissolves to at least one of:
expose a microstructure; expose a further coating; and, expose a
material; provides stimulation to the subject; contains a material;
and, selectively releases a material; acts as a barrier to preclude
at least one substance from the microstructures; and, includes at
least one of: polyethylene; polyethylene glycol; polyethylene
oxide; zwitterions; peptides; hydrogels; and, self-assembled
monolayer.
[0076] In one embodiment the microstructures are configured to
deliver stimulation to trigger a biological response in the
subject.
[0077] In one embodiment the system is configured to perform
repeated measurements over a time period.
[0078] In one embodiment the time period is at least one of: at
least one minute; at least one hour; at least one day; and, at
least one week.
[0079] In one embodiment the microstructures are configured to
remain in the subject during the time period.
[0080] In one embodiment the microstructures are configured to be
removed when measurements are not being performed.
[0081] In one embodiment the actuator is configured to apply a
force to the substrate to at least one of: sense tissue mechanical
properties; provide mechanical stimulation; attract or repel
substances; trigger a biological response; release material from a
coating on at least some microstructures; disrupt a coating on at
least some microstructures; dissolve a coating on at least some
microstructures; dislodge a coating on the microstructures; release
a coating on at least some microstructures. cause the
microstructures to penetrate the barrier; retract the
microstructures from the barrier; and, retract the microstructures
from the subject.
[0082] In one embodiment the system includes a monitoring device
and a patch including the substrate and microstructures.
[0083] In one embodiment the monitoring device includes the
actuator.
[0084] In one embodiment the system is at least partially wearable.
It will be appreciated that the broad forms of the invention and
their respective features can be used in conjunction and/or
independently, and reference to separate broad forms is not
intended to be limiting. Furthermore, it will be appreciated that
features of the method can be performed using the system or
apparatus and that features of the system or apparatus can be
implemented using the method.
BRIEF DESCRIPTION OF THE DRAWINGS
[0085] Various examples and embodiments of the present invention
will now be described with reference to the accompanying drawings,
in which: --
[0086] FIG. 1 is a schematic diagram of an example of a system for
performing measurements on a biological subject including an
actuator arrangement;
[0087] FIG. 2 is a flow chart of an example of a process for
performing measurements on a biological subject;
[0088] FIG. 3A is a schematic diagram of a further example of a
system for performing measurements on a biological subject;
[0089] FIG. 3B is a schematic underside view of an example of a
patch for the system of FIG. 3A;
[0090] FIG. 3C is a schematic plan view of the patch of FIG.
3B;
[0091] FIG. 3D is a schematic side view of an example of a housing
arrangement for the system of FIG. 3A;
[0092] FIG. 3E is a schematic plan view of the housing arrangement
of FIG. 3D;
[0093] FIG. 3F is a schematic side view of an example of a flexible
segmented substrate arrangement;
[0094] FIG. 3G is a schematic side view of a further example of a
flexible segmented substrate arrangement;
[0095] FIG. 3H is a schematic side view of a further example of a
flexible segmented substrate arrangement;
[0096] FIG. 3I is a schematic side view of a further example of a
flexible segmented substrate arrangement;
[0097] FIG. 3J is a schematic side view of an example actuator
arrangement;
[0098] FIG. 3K is a schematic side view of a further example
actuator arrangement;
[0099] FIG. 4A is a schematic side view of a first example of a
microstructure configuration;
[0100] FIG. 4B is a schematic side view of a second example of a
microstructure configuration;
[0101] FIG. 4C is a graph illustrating the electric field between
closely spaced electrodes;
[0102] FIG. 4D is a graph illustrating the electric field between
distant spaced electrodes;
[0103] FIG. 5A is a schematic side view of an example of a plate
microstructure;
[0104] FIG. 5B is a schematic front view of the microstructure of
FIG. 5A;
[0105] FIG. 5C is a schematic underside view of an example of a
patch including the microstructure of FIG. 5A;
[0106] FIG. 5D is a schematic perspective topside view of an
example of substrate including pairs of blade microstructures of
FIGS. 5A and 5B;
[0107] FIG. 5E is a schematic front view of an example of a blade
microstructure;
[0108] FIG. 5F is a schematic perspective topside view of an
example of substrate including blade microstructures;
[0109] FIG. 5G is a schematic plan view of an example of a
hexagonal grid microstructure array;
[0110] FIG. 5H is a schematic plan view of an alternative example
of a grid of pairs of microstructures;
[0111] FIG. 51 is a schematic plan view of the grid of FIG. 5H
showing example connections;
[0112] FIG. 5J is a schematic perspective view of an example of a
grid of pairs of microstructures;
[0113] FIG. 5K is an image of an example of a patch including
arrays of pairs of angularly offset plate microstructures;
[0114] FIG. 5L is a schematic side view of a specific example of a
plate microstructure;
[0115] FIG. 5M is a schematic perspective view of the plate
microstructure of FIG. 51;
[0116] FIG. 5N is a schematic side view of an example of a pair of
microstructures inserted into a subject for epidermal
measurement;
[0117] FIG. 5O is a schematic side view of an example of a pair of
microstructures inserted into a subject for dermal measurement;
[0118] FIG. 6A is a schematic side view of a second example of a
microstructure;
[0119] FIG. 6B is a schematic front view of the microstructure of
FIG. 6A;
[0120] FIG. 7A is a schematic diagram of a third example of a
microstructure;
[0121] FIG. 7B is a schematic diagram of a modified version of the
microstructure of FIG. 7A;
[0122] FIG. 8A is a schematic side view of an example of a first
step of a microstructure construction technique;
[0123] FIG. 8B is a schematic side view of an example of a second
step of a microstructure construction technique;
[0124] FIG. 8C is a schematic side view of an example of a third
step of a microstructure construction technique;
[0125] FIG. 8D is a schematic side view of a first example of a
microstructure configuration created using the construction
technique of FIGS. 8A to 8C;
[0126] FIG. 8E is a schematic side view of a second example of a
microstructure configuration created using the construction
technique of FIGS. 8A to 8C;
[0127] FIG. 9 is a schematic diagram of an example of a distributed
computer architecture;
[0128] FIG. 10 is a schematic diagram of an example of a processing
system;
[0129] FIG. 11 is a schematic diagram of an example of a client
device;
[0130] FIGS. 12A and 12B are a flow chart of an example of a
process for performing a measurement on a biological subject;
[0131] FIG. 13 is a flow chart of an example of a process for
creating a subject record;
[0132] FIGS. 14A and 14B are a flow chart of a specific example of
a process for performing measurements in a biological subject;
[0133] FIG. 15A is a schematic perspective topside view of an
example of a patch including a substrate incorporating
microstructure electrodes and a substrate coil;
[0134] FIG. 15B is a schematic diagram of an equivalent circuit
representing the electrical response of the patch of FIG. 15A;
[0135] FIG. 15C is a graph illustrating the response to a drive
signal for the patch of FIG. 15A;
[0136] FIG. 15D is a graph illustrating the resonance response of
the patch of FIG. 15A;
[0137] FIG. 15E is a schematic perspective topside view of an
example of a dual patch arrangement;
[0138] FIG. 15F is a graph illustrating an example of drive signal
attenuation for the dual patch configuration of FIG. 15E;
[0139] FIGS. 16A to 16P are schematic diagrams illustrating steps
in an example manufacturing process;
[0140] FIGS. 17A to 17D are micrograph images of examples of
microstructures manufactured using the approach of FIGS. 16A to
16P;
[0141] FIGS. 18A to 18L are schematic diagrams illustrating steps
in an example manufacturing process;
[0142] FIGS. 19A and 19B are micrograph images of examples of
microstructures manufactured using the approach of FIGS. 18A to
18L;
[0143] FIGS. 19C and 19D are micrograph images of further examples
of microstructures manufactured using the approach of FIGS. 18A to
18L;
[0144] FIGS. 20A and 20B are micrograph images of examples of
partially coated microstructures;
[0145] FIGS. 21A to 21F are images illustrating an example of
penetration of porcine ear by a microstructure without
vibration;
[0146] FIGS. 21G to 21K are images illustrating an example of
penetration of porcine ear by a microstructure with vibration;
[0147] FIGS. 22A to 22D are images illustrating examples of
penetration of the stratum corneum for patches having a
microstructure density of 188 per cm.sup.2, 300 per cm.sup.2, 550
per cm.sup.2, respectively;
[0148] FIG. 23A is a graph showing a depth of penetration for
different microstructure and force configurations;
[0149] FIG. 23B is a graph showing a depth of penetration for
application with or without vibration;
[0150] FIG. 24A is an image of a microstructure patch application
site on a human forearm skin immediately post-removal;
[0151] FIG. 24B is a Scanning Electron Micrograph of a
microstructure after application to human skin;
[0152] FIG. 25A is a graph of example qualitative scores of
erythema at microstructure patch application sites on human forearm
skin from a first study;
[0153] FIG. 25B is a graph of example qualitative scores of
erythema at microstructure patch application sites on human forearm
skin from a second study;
[0154] FIG. 26A is a Scanning Electron Micrographs of
microstructure prior to application into human forearm skin;
[0155] FIG. 26B is a Scanning Electron Micrographs of the
microstructure of FIG. 26A post application into human forearm
skin;
[0156] FIG. 26C is a Scanning Electron Micrographs of a
microstructure patch post application into human forearm skin;
[0157] FIG. 26D is a Scanning Electron Micrographs of
microstructure prior to application into human forearm skin;
[0158] FIG. 26E is a Scanning Electron Micrographs of the
microstructure of FIG. 26D post application into human forearm
skin;
[0159] FIG. 26F is a Scanning Electron Micrographs of a
microstructure patch post application into human forearm skin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0160] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by those
of ordinary skill in the art to which the invention belongs.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, preferred methods and materials are described.
For the purposes of the present invention, the following terms are
defined below.
[0161] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e. to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0162] The terms "about" and "approximately" are used herein to
refer to conditions (e.g. amounts, levels, concentrations, time,
etc.) that vary by as much as 20% (i.e. .+-.20%), especially by as
much as 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a specified
condition.
[0163] As used herein, the term "analyte" refers to a naturally
occurring and/or synthetic compound, which is a marker of a
condition (e.g., drug abuse), disease state (e.g., infectious
diseases), disorder (e.g., neurological disorders), or a normal or
pathologic process that occurs in a subject (e.g., drug
metabolism), or a compound which can be used to monitor levels of
an administered or ingested substance in the subject, such as a
medicament (substance that treats, prevents and/or alleviates the
symptoms of a disease, disorder or condition, e.g., drug, vaccine
etc.), an illicit substance (e.g. illicit drug), a non-illicit
substance of abuse (e.g. alcohol or prescription drug taken for
non-medical reasons), a poison or toxin (including an environmental
contaminant), a chemical warfare agent (e.g. nerve agent, and the
like) or a metabolite thereof. The term "analyte" can refer to any
substance, including chemical and/or biological agents that can be
measured in an analytical procedure, including nucleic acids,
proteins, illicit drugs, explosives, toxins, pharmaceuticals,
carcinogens, poisons, allergens, and infectious agents, which can
be measured in an analytical procedure. The analyte may be a
compound found directly in a sample such as biological tissue,
including body fluids (e.g. interstitial fluid), from a subject,
especially in the dermis and/or epidermis. In particular
embodiments, the analyte is a compound found in the interstitial
fluid. In some embodiments, the analyte is a compound with a
molecular weight in the range of from about 30 Da to about 100 kDa,
especially about 50 Da to about 40 kDa. Other suitable analytes are
as described herein.
[0164] As used herein, the term "and/or" refers to and encompasses
any and all possible combinations of one or more of the associated
listed items, as well as the lack of combinations when interpreted
in the alternative (or).
[0165] As used herein, the term "aptamer" refers to a
single-stranded oligonucleotide (e.g. DNA or RNA) that binds to a
specific target molecule, such as an analyte. An aptamer may be of
any size suitable for binding such target molecule, such as from
about 10 to about 200 nucleotides in length, especially from about
30 to about 100 nucleotides in length.
[0166] The term "bind" and variations such as "binding" are used
herein to refer to an interaction between two substances, such as
an analyte and an aptamer or an analyte and a molecularly imprinted
polymer. The interaction may be a covalent or non-covalent
interaction, particularly a non-covalent interaction.
[0167] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps. Thus, the use of the term
"comprising" and the like indicates that the listed integers are
required or mandatory, but that other integers are optional and may
or may not be present. By "consisting of" is meant including, and
limited to, whatever follows the phrase "consisting of". Thus, the
phrase "consisting of" indicates that the listed elements are
required or mandatory, and that no other elements may be present.
By "consisting essentially of" is meant including any elements
listed after the phrase, and limited to other elements that do not
interfere with or contribute to the activity or action specified in
the disclosure for the listed elements. Thus, the phrase
"consisting essentially of" indicates that the listed elements are
required or mandatory, but that other elements are optional and may
or may not be present depending upon whether or not they affect the
activity or action of the listed elements.
[0168] The term "plurality" is used herein to refer to more than
one, such as 2 to 1.times.10.sup.15 (or any integer therebetween)
and upwards, including 2, 10, 100, 1000, 10000, 1.times.10.sup.6,
1.times.10.sup.7, 1.times.10.sup.8, 1.times.10.sup.9,
1.times.10.sup.10, 1.times.10.sup.11, 1.times.10.sup.12,
1.times.10.sup.13, 1.times.10.sup.14, 1.times.10.sup.15, etc. (and
all integers therebetween).
[0169] As used herein, the term "predetermined threshold" refers to
a value, above or below which indicates the presence, absence or
progression of a disease, disorder or condition; the presence or
absence of an illicit substance or non-illicit substance of abuse;
or the presence or absence of a chemical warfare agent, poison
and/or toxin. For example, for the purposes of the present
invention, a predetermined threshold may represent the level or
concentration of a particular analyte in a corresponding sample
from an appropriate control subject, such as a healthy subject, or
in pooled samples from multiple control subjects or medians or
averages of multiple control subjects. Thus, a level or
concentration above or below the threshold indicates the presence,
absence or progression of a disease, disorder or condition; the
presence or absence of an illicit substance or non-illicit
substance of abuse; or the presence or absence of a chemical
warfare agent, poison and/or toxin, as taught herein. In other
examples, a predetermined threshold may represent a value larger or
smaller than the level or ratio determined for a control subject so
as to incorporate a further degree of confidence that a level or
ratio above or below the predetermined threshold is indicative of
the presence, absence or progression of a disease, disorder or
condition; the presence or absence of an illicit substance or
non-illicit substance of abuse; or the presence or absence of a
chemical warfare agent, poison and/or toxin. Those skilled in the
art can readily determine an appropriate predetermined threshold
based on analysis of samples from appropriate control subjects.
[0170] The terms "selective" and "selectivity" as used herein refer
to molecularly imprinted polymers or aptamers that bind an analyte
of interest without displaying substantial binding of one or more
other analytes. Accordingly, a molecularly imprinted polymer or
aptamer that is selective for an analyte, such as troponin or a
subunit thereof, exhibits selectivity of greater than about 2-fold,
5-fold, 10-fold, 20-fold, 50-fold, 100-fold or greater than about
500-fold with respect to binding of one or more other analytes.
[0171] The term "subject" as used herein refers to a vertebrate
subject, particularly a mammalian subject, for whom monitoring
and/or diagnosis of a disease, disorder or condition is desired.
Suitable subjects include, but are not limited to, primates; avians
(birds); livestock animals such as sheep, cows, horses, deer,
donkeys and pigs; laboratory test animals such as rabbits, mice,
rats, guinea pigs and hamsters; companion animals such as cats and
dogs; bats and captive wild animals such as foxes, deer and
dingoes. In particular, the subject is a human.
System for Performing Measurements
[0172] An example of a system for performing measurements on a
biological subject will now be described with reference to FIG.
1.
[0173] In this example, the system includes at least one substrate
111 having one or more microstructures 112. In use, the
microstructures are configured to breach a functional barrier
associated with a subject. In the current example, the functional
barrier is the stratum corneum SC, and the microstructures are
configured to breach the stratum corneum SC by penetrating the
stratum corneum SC and entering at least the viable epidermis VE.
In one particular example, the microstructures are configured to
not penetrate a boundary between the viable epidermis VE and the
dermis D, although this is not essential and structures that
penetrate into the dermis could be used as will be described in
more detail below.
[0174] Whilst this example is described with respect to breaching
of the stratum corneum SC, it will be appreciated that this is not
essential, and the techniques could equally be applied to other
functional barriers. In this regard, a functional barrier will be
understood to include any structure, boundary, or feature, whether
physical or otherwise, that prevents passage of signals, and/or
analytes, such as biomarkers. For example, functional barriers
could include one or more layers, a mechanical discontinuity, such
as a discrete change in tissue mechanical properties, a tissue
discontinuity, a cellular discontinuity, a neural barrier, a sensor
barrier, a cellular layer, skin layers, mucosal layers, internal or
external barriers, an inner barrier within an organ, an outer
barrier of organs other than the skin, epithelial layers or
endothelial layers, or the like. Functional barriers could also
include other internal layers or boundaries, including optical
barriers such as a melanin layer, electrical barriers, molecular
weight barriers that prevent passage of a biomarkers with certain
molecular weights, a basal layer boundary between the viable
epidermis and dermis, or the like.
[0175] The nature of the microstructure will vary depending upon
the preferred implementation. In one example, the microstructures
could include needles, but this is not essential and more typically
structures, such as plates, blades, or the like, are used, as will
be described in more detail below.
[0176] The substrate and microstructures could be manufactured from
any suitable material, and the material used may depend on the
intended application, for example depending on whether there is a
requirement for the structures to be optically and/or electrically
conductive, or the like. The substrate can form part of a patch
110, which can be applied to a subject, although other arrangements
could be used for example, having the substrate form part of a
housing containing other components.
[0177] In one example at least one sensor 121 is provided, which is
operatively connected to at least one microstructure 112, thereby
allowing response signals to be measured from respective
microstructures 112. In this regard, the term response signal will
be understood to encompass signals that are intrinsic within the
subject, such ECG (Electrocardiograph) signals, or the like, or
signals that are induced as a result of the application of
stimulation, such as bioimpedance signals, or the like.
[0178] The nature of the sensor will vary depending on the
preferred implementation and the nature of the sensing being
performed. For example, the sensing could include sensing
electrical signals, in which case the sensor could be a voltage or
current sensor, or the like. Alternatively, optical signals could
be sensed, in which case the sensor could be an optical sensor,
such as a photodiode, CCD (Charge Coupled Device) array, or
similar, whilst temperature signals could be sensed using a
thermistor or the like.
[0179] The manner in which the sensor 121 is connected to the
microstructure(s) 112 will also vary depending on the preferred
implementation. In one example, this is achieved using connections
between the microstructure(s) 112 and the sensor, with the nature
of the connections varying depending upon the signals being sensed,
so that the connections could include electrically conductive
elements to conduct electrical signals, a wave guide, optical fibre
or other conductor to conduct electromagnetic signals, or thermal
conductor to conduct thermals signals. Connections could also
include wireless connections, allowing the sensor to be located
remotely. Ionic connections could also be used. Furthermore,
connections could be provided as discrete elements, although in
other examples, the substrate provides the connection, for example,
if the substrate is made from a conductive plate which is then
electrically connected to all of the microstructures. As a further
alternative, the sensor could be embedded within or formed from
part of the microstructure, in which connections may not be
required.
[0180] The sensor 121 can be operatively connected to all of the
microstructures 112, with connections being collective and/or
independent. For example, one or more sensors could be connected to
different microstructures to allow different measured response
signals to be measured from different groups of microstructures
112. However, this is not essential, and any suitable arrangement
could be used.
[0181] In addition to providing sensing, in some examples, the
microstructures 112 could additionally and/or alternatively be
configured to provide stimulation. For example, microstructures
could be coupled to a signal generator that generates a stimulatory
signal, as will be described in more detail below. Such stimulation
could again include electrical stimulation, using a voltage or
current source, optical stimulation, using a visible or non-visible
radiation source, such as an LED or laser, thermal stimulation, or
the like, and could be delivered via the same microstructures used
for measuring response signals, or different microstructures,
depending on the preferred implementation. Additionally and/or
alternatively, stimulation could be achieved using other
techniques, such as through exposure of the subject to the
microstructures and materials thereon or therein. For example,
coatings can be applied to the microstructures, allowing material
to be delivered into the subject beyond the barrier, thereby
stimulating a response within the subject.
[0182] These options allow a range of different types of sensing to
be performed, including detecting electrical signals within the
body, such as ECG signals, plethysmographic signals,
electromagnetic signals, or electrical potentials generated by
muscles, neural tissue, blood, or the like, detecting
photoplethysmographic effects, electromagnetic effects, such as
fluorescence, detecting mechanical properties, such as stress or
strain, or the like. Sensing could include detecting the body's
response to applied electrical signals, for example to measure
bioimpedance, bioconductance, or biocapacitance, detecting the
presence, absence, level or concentration of analytes, for example
by detecting electrical or optical properties, or the like.
[0183] The system further includes one or more electronic
processing devices 122, which can form part of a measuring device,
and/or could include electronic processing devices forming part of
one or more processing systems, such as computer systems, servers,
client devices, or the like as will be described in more detail
below. In use, the processing devices 122 are adapted to receive
signals from the sensor 121 and either store or process the
signals. For ease of illustration the remaining description will
refer generally to a processing device, but it will be appreciated
that multiple processing devices could be used, with processing
distributed between the devices as needed, and that reference to
the singular encompasses the plural arrangement and vice versa.
[0184] Additionally, the system includes an actuator 126, such as
piezoelectric actuator, vibratory motor, linear actuator, or
similar, which is capable of applying a force to the substrate to
cause the microstructures to breach the functional barrier, and in
one particular example, at least one of pierce and penetrate the
stratum corneum.
[0185] An example of the manner in which this is performed will now
be described with reference to FIG. 2.
[0186] In particular, in this example, at step 200, the substrate
is applied to the subject so that the one or more microstructures
breach, and in one example, penetrate the functional barrier. For
example, when applied to skin, the microstructures could penetrate
the stratum corneum and enter the viable epidermis as shown in FIG.
1. This could be achieved manually and/or through the use of an
actuator, to help ensure successful penetration.
[0187] At step 210, response signals within the subject are
optionally measured, with signals indicative of the measured
response signals being provided to the electronic processing device
112. This may be performed following application of stimulation,
although this is not essential and will vary depending on the
nature of the sensing being performed.
[0188] The one or more processing devices then control the actuator
at step 220, to allow the microstructures to breach the barrier. In
one example, this is performed based on analysis of the measured
response signals, so that the actuator can be controlled based on a
depth or degree of penetration. For example, changes in response
signals can be used to identify when the functional barrier is
breached, with the force being controlled taking this into
account.
[0189] The analysis can be performed in any suitable manner, and
this will vary depending on nature of the measurements being
performed. For example, this could involve examining measured
response signal values and using these to interpret the depth of
penetration of the microstructures.
[0190] Measured response signals could also be analysed to
calculate an indicator indicative of a health status, including the
presence, absence, degree or prognosis of one or more medical
conditions, a prognosis associated with a medical condition, a
presence, absence, level or concentration of a biomarker, a
presence, absence, level or concentration of an analyte, a
presence, absence or grade of cancer, fluid levels in the subject,
blood oxygenation, a tissue inflammation state, bioelectric
activity, such as nerve, brain, muscle or heart activity or a range
of other health states. This could be achieved by monitoring
changes in the values over time, and may involve comparison to
values measured for reference subjects having known medical
conditions. Additionally, and/or alternatively, the indicator could
be indicative of measured parameters associated with the subject,
such as measured levels or concentrations of analytes or other
biomarkers
[0191] In any event, it will be appreciated that the above
described system operates by providing microstructures that are
configured to breach a barrier, such as the stratum corneum,
allowing these to be used to measure response signals within the
subject, such as within the epidermis and/or dermis. These response
signals can then be processed and subsequently analysed, allowing a
variety of values to be derived, which could be indicative of
specific measurements, or one or more aspects of subject
health.
[0192] For example, the system can be configured to measure an
analyte level or concentration, such as the level or concentration
of a specific biomarker. Response signals could also be used to
generate a visualization, a spatial mapping in 1, 2 or 3
dimensions, details of mechanical properties, forces, pressures,
muscle movement, blood pulse wave, an analyte concentration such as
the presence, absence, level or concentration of specific
biomarkers, a blood oxygen saturation, a bioimpedance, a
biocapacitance, a bioconductance or electrical signals within the
body, such as ECG (Electrocardiography) signals.
[0193] In one example, the system can be configured so that
measurements are performed at a specific location within the
subject, such as within the epidermis only, the dermis only, or the
like. This allows targeted analyte detection to be performed with a
high level of accuracy, providing higher quality data for more
precise measures of analytes. Furthermore, constraining the
location in which measurements are performed ensures these are
repeatable, allowing for more accurate longitudinal monitoring.
[0194] In contrast to traditional approaches, breaching and/or at
least partially penetrating a functional barrier, such as the
stratum corneum, allows measurements to be performed from within or
under the barrier, and in particular within the epidermis and/or
dermis, resulting in a significant improvement in the quality and
magnitude of response signals that are detected. In particular,
this ensures that the response signals accurately reflect
conditions within the human body, and in particular within the
epidermis and/or dermis, such as the presence, absence, level or
concentration of biomarkers, the impedance of interstitial fluid,
or the like, as opposed to traditional external measurements, which
are unduly influenced by the environment outside the barrier, such
as the physical properties of the skin surface, such as the skin
material properties, presence or absence of hair, sweat, mechanical
movement of the applied sensor, or the like. Additionally, by
penetrating the stratum corneum but not the dermis, this allows
measurements to be constrained to the epidermis only, thereby
avoiding interference from fluid level changes in the dermis.
[0195] For example, this allows accurate measurement of high
molecular weight biomarkers to be performed, which would otherwise
only pass through the skin poorly. A good example of this, is
glucose, which whilst present externally, such as in sweat, is
typically only present in low concentrations, and often time
delayed, meaning the concentration in sweat does not necessarily
reflect current glucose levels within the body. In contrast, by
breaching the barrier, in this case the stratum corneum, this
allows far more accurate measurements to be performed. It will be
appreciated that similar considerations apply to a wide range of
different biomarkers or signals, and associated barriers that
otherwise prevent accurate measurement of the biomarkers or
signals.
[0196] For example, in the case of impedance measurements
microstructure electrodes tend to measure different impedances as
opposed to standard surface electrodes, which is indicative of the
fact that the microstructure electrodes do not measure skin
impedance, meaning the measured impedance is more indicative of
conditions within the body. As the contribution of the skin surface
impedance is significant in magnitude this can result in changes in
impedance within the body being masked, meaning skin-based
measurements are less likely to be able to detect meaningful
changes. It is also noticeable that the measurements are more
consistent at different frequencies, indicating that they are less
prone to noise.
[0197] Additionally, in some examples, the microstructures only
penetrate the barrier a sufficient distance to allow a measurement
to be made. For example, in the case of skin, the microstructures
are typically configured to enter the viable epidermis and not
enter the dermal layer. This results in a number of improvements
over other invasive techniques, including avoiding issues
associated with penetration of the dermis, such as pain caused by
exposure of nerves, erythema, petechiae, or the like. Avoiding
penetrating the dermal boundary also significantly reduces the risk
of infection, allowing the microstructures to remain embedded for
prolonged periods of time, such as several days, which in turn can
be used to perform longitudinal monitoring over a prolonged time
periods. However, in some instances, such as when detecting
troponin or a subunit thereof, penetration of the dermal barrier
may be required.
[0198] It will be appreciated that the ability of the
microstructures to remain in-situ is particularly beneficial, as
this ensures that measurements are made at the same site within the
subject, which reduces inherent variability arising from
inaccuracies of replacement of measuring equipment which can arise
using traditional techniques. Despite this, it will be appreciated
that the system can be used in other manners, for example to
perform single time point monitoring or the like.
[0199] In one example, this allows the arrangement to be provided
as part of a wearable device, enabling measurements to be performed
that are significantly better than existing surface-based
measurement techniques, for example by providing access to signals
or biomarkers that cannot otherwise pass through the barrier, but
whilst allowing measurements to be performed whilst the subject is
undergoing normal activities and/or over a prolonged period of
time. This in turn enables measurements to be captured that are
more accurately reflective of the health or other status of the
subject. For example, this allows variations in a subject's
condition during a course of the day to be measured, and avoids
measurements being made under artificial conditions, such as within
a clinic, which are not typically indicative of the actual
condition of the subject. This also allows monitoring to be
performed substantially continuously, which can allow conditions to
be detected as they arise, for example, in the case of myocardial
infarction, cardiovascular disease, vomiting, diarrhoea, or
similar, which can allow more rapid intervention to be sought.
[0200] Additionally, or alternatively, the microstructures can be
used to deliver stimulation or therapy to the subject, with again
this being more effective due to the ability to deliver therapy or
stimulation through the barrier.
[0201] Irrespective of whether or not the system is used to perform
measurements and/or deliver therapy or stimulation, the ability to
breach the functional barrier allows improved effectiveness to be
achieved. Accordingly, in one example, an actuator is provided,
which is configured to apply a force to the substrate and hence
microstructures, aiding in breaching of the barrier. Furthermore,
in some examples, feedback from measured signals can be used to
increase the effectiveness of the process.
[0202] The above described system can be applied to any part of the
body, and hence could be used with a wide range of different
functional barriers. For example, the functional barrier could be
an internal or external barrier, a skin layer, a mucosal layer, an
inner barrier within an organ, an outer barrier of an organ, an
epithelial layer, an endothelial layer, a melanin layer, an optical
barrier, an electrical barrier, molecular weight barrier, basal
layer or the stratum corneum. Thus, the microstructures could be
applied to the buccal mucosa, the eye, or another epithelial layer,
endothelial layer, or the like. The following examples will focus
specifically on application to the skin, with the functional
barrier including some or all of the stratum corneum, but it will
be appreciated that this is intended to be illustrative and is not
intended to be limiting.
[0203] Further variations will become apparent from the following
description.
[0204] In one example, the system includes a signal generator
operatively connected to at least one microstructure to apply
stimulation, typically by applying a stimulatory signal to the
microstructure. Again, the manner in which the signal generator is
connected will vary depending on the preferred implementation, and
this could be achieved via connections, such as wired or wireless
connections and/or integrating the signal generator into the
substrate and/or microstructures. Example connection types include
mechanical, magnetic, thermal, electrical, electromagnetic,
optical, or the like.
[0205] The nature of the stimulatory signal and the manner in which
this is applied will vary depending upon the preferred
implementation and this could include any one or more of
biochemical, chemical, mechanical, magnetic, electromagnetic,
electrical, optical, thermal, or other signals. The stimulatory
signal could be used to allow the response signal to be measured
and/or could be used to trigger a biological response, which is
then measured. For example this can be used to cause
electroporation, to induce local mediators of inflammation, which
can in turn release biomarkers, allowing levels or concentrations
of these to be measured. In this regard, electroporation, or
electropermeabilization, involves applying an electrical field to
cells in order to increase the permeability of the cell membrane,
allowing chemicals, drugs, or DNA to be introduced into the cell.
In another example, stimulation can be used to disrupt a boundary
within the subject, for example disrupting a dermal boundary
allowing biomarkers within the dermal layer to be detected in the
viable epidermis, without requiring penetration of the dermal layer
by the microstructures. In a further example, stimulation can be
used to trigger additional effects. So, for example, an electrical
or mechanical signal could be used to disrupt a coating on the
microstructures, causing material to be released, which can in turn
a chemical or other stimulation.
[0206] Stimulatory signals could also be applied to the
microstructures to alter the microstructure form or function. For
example, polymer microstructures could be induced to grow or shrink
along their length or width with an applied electric field or
temperature, whilst microstructures could be configured to move
between a retracted flat position and an extended upright position,
in order to penetrate and then retract from the skin or other
barrier.
[0207] In one example, operation of the signal generator is
controlled by the processing device, allowing the processing device
to control the signal generator to thereby cause a measurement to
be performed, for example by applying an electrical signal to allow
an impedance measurement to be performed. Additionally, and/or
alternative the processing device could control the signal
generator in accordance with measured response signals, for
example, allowing stimulation to be applied to the subject and/or
microstructures once certain criteria are met. For example, in
theranostic applications, a signal applied to microstructures can
be used to release therapeutic materials. In this example, the
processing device can monitor response signals and use these to
assess when an intervention is required, and then control the
signal generator to trigger the release. In one example, such
control could be performed in accordance with a dosing regime, for
example specifying a dose and timing of delivery of the dose, once
it has been determined that therapy is required. In this example,
the dosing regimen could be predetermined and stored onboard or
could be manually input by a clinician or other individual, as
needed.
[0208] As mentioned above, the signal generator and/or sensor can
be connected to the microstructures via connections. The nature of
the connections will vary depending on the preferred implementation
and the nature of the signal. For example, if the signal is an
optical or other electromagnetic signal, a waveguide, fibre optic
cable, or other electromagnetic conductor can be used. In the case
of electrical signals, the connections can be conductive
connections, such as wires, or conductive tracks on a substrate, or
could be formed by a conductive substrate. Connections could also
include wireless connections, such as short-range radio frequency
wireless connections, inductive connections, or the like.
Connections could also be mechanical, magnetic, thermal, or the
like.
[0209] In one example, inductive connections can be used to
transmit signals and power, so that for example, inductive coupling
could be used to power electronic circuits mounted on the
substrate. This could be used to allow basic processing to be
performed on board the substrate, such as amplifying and process
impedance changes, using a simple integrated circuit or similar,
without requiring an in-built power supply on the substrate.
[0210] In one example, the system can include response
microstructures used to measure response signals and/or stimulation
microstructures used to apply stimulation signals to the subject.
Thus, stimulation and response could be measured via different
microstructures, in which case the substrate typically incorporates
response connections for allowing response signals to be measured
and stimulation connections allowing stimulation signals to be
applied. In some examples, multiple stimulation and response
connections are provided, allowing different measurements to be
performed via different connections. For example, different types
of measurements could be performed via different microstructures or
different parts of given microstructures, to enable multi-modal
sensing. Additionally and/or alternatively, the same type of
measurements could be performed at different locations and/or
depths, for example to identify localised issues, such as the
presence of skin cancers or similar. In other cases, stimulation
and measurement could be performed via the same connections, for
example when making bipolar impedance measurements.
[0211] Signals could be applied to or measured from individual
microstructures and/or to different parts of microstructures, which
can be useful to discern features at different locations and/or
depths within the body. This can be used for example to perform
mapping or tomography, for example to produce images wherein the
image contrast or colour is proportional to the levels or
concentrations of one or more analytes or the change in a physical
property such as bioimpedance. Additionally, and/or alternatively,
signals could be applied to or measured from multiple
microstructures collectively, which can be used to improve signal
quality, or perform measurements, such as bipolar, tetra-polar, or
other multi-polar impedance measurements. Additionally and/or
alternatively, microstructures might be used for both measuring and
stimulation, for example applying a signal to a microstructure and
then subsequently measuring a response therefrom.
[0212] In one particular example, sensors and/or signal generators
can be connected to microstructures via one or more switching
devices, such as multiplexers, allowing signals to be selectively
communicated between the sensor or signal generator and different
microstructures. The processing device is typically configured to
control the switches, allowing a variety of different sensing and
stimulation to be achieved under control of the processing device.
In one example, this allows at least some electrodes can be used
independently of at least some other electrodes. This ability to
selectively interrogate different electrodes can provide
benefits.
[0213] For example, this allows different electrodes to have
different functionality, for example by having different electrodes
functionalized with different coatings, and then interrogated or
stimulated as needed, so that different measurements can be
performed as required. Additionally, and/or alternatively, this
allows different measurements to be performed via different
microstructures, for example to perform spatial discrimination and
hence mapping. For example, interrogating electrodes at different
locations on a patch, enables a map of measurements at different
locations to be constructed, which can in turn be used to localise
an effect, so as the presence of analytes or specific objects, such
as lesions or cancer. Furthermore, this allows stimulation to be
delivered to different microstructures. For example, in theranostic
embodiments, different therapeutic materials or doses could be
associated with different microstructures, so selectively
stimulating different microstructures allows a range of different
interventions to be performed. In some example, different
microstructures could be used for different purposes, so that some
microstructures are used for sensing, whilst others are used for
delivering stimulation and/or therapy.
[0214] In another example, as described in more detail below, when
electrodes are provided as pairs, this allows some pairs of
electrodes to be used independently of other pairs. In one
particular example, electrodes and/or pairs of electrodes, can be
arranged in rows, and this can allows measurements to be performed
on a row by row basis, although this is not essential and other
groupings could be used.
[0215] The nature of the substrate and/or microstructures will vary
depending upon the preferred implementation. For example, substrate
and/or microstructures could be made from or contain fabric, woven
fabric, electronic fabric, natural fibres, silk, organic materials,
natural composite materials, artificial composite materials,
ceramics, stainless steel, ceramics, metals, such as stainless
steel, titanium or platinum, polymers, such as rigid or semi-rigid
plastics, including doped polymers, silicon or other
semiconductors, including doped semiconductors, organosilicates,
gold, silver, carbon, carbon nano materials, or the like. The
substrate and microstructures could be made from similar and/or
dissimilar materials, and could be integrally formed, or made
separately and bonded together. Microstructures can also be
provided on one or more substrates, so for example, signals could
be measured or applied between microstructures on separate
substrates.
[0216] It will be appreciated that the particular material used
will depend on the intended application, so for example different
materials will be used if the microstructure needs to be conductive
as opposed to insulative. Insulating materials, such as polymers
and plastics could be doped so as to provide required conductivity,
for example via doping with micro or nano sized metal particles, or
conductive composite polymers could be used such as PEDOT:PSS
(poly(3,4-ethylenedioxythiophene)polystyrene). If doping is used,
this could involve using graphite or graphite derivates, including
2D materials such as graphene and carbon nanotubes, with these
materials also being useable as stand-alone materials or as dopants
in blends with polymers or plastics.
[0217] The substrate and microstructures can be manufactured using
any suitable technique. For example, in the case of silicon-based
structures, this could be performed using etching techniques.
Polymer or plastic structures could be manufactured using additive
manufacturing, such as 3D printing, or moulding. In one particular
example, a mould is filled with a suitable filling material, such
as a solution containing a material such as an active compound
and/or sugar-based excipient, such as carboxy-methylcellulose
(CMC), or one or more polymers, or the like, which is then cured
and removed. It will also be appreciated that the filling material
may include any required probes, reagents, or the like that are to
be contained within the structures, as will be discussed in more
detail below. Photosensitive polymers might be used, such as
photoresists, including SU8 or polyimides, for direct patterning of
electrodes on the substrate or to make microstructures. Successive
layers of photosensitive resists, polymers, metals, or the like,
can be deposited and/or selectively removed to produce bespoke 3D
microstructure geometries.
[0218] In one example, the substrate could be at least partially
flexible in order to allow the substrate to conform to the shape of
a subject and thereby ensure penetration of the microstructures
into the viable epidermis and/or dermis, or other functional
barrier. In this example, the substrate could potentially be a
textile or fabric, with electrodes and circuitry woven in, or
multiple substrates could be mounted on a flexible backing, to
provide a segmented substrate arrangement. Alternatively, the
substrate could be shaped to conform to a shape of the subject, so
that the substrate is rigid but nevertheless ensures penetration of
the microstructures.
[0219] In preferred examples, the substrate and microstructures are
formed from one or more of metal, polymer or silicon.
[0220] The microstructures could have a range of different shapes
and could include ridges, needles, plates, blades, or similar. In
this regard, the terms plates and blades are used interchangeably
to refer to microstructures having a width that is of a similar
order of magnitude in size to the length, but which are
significantly thinner. The microstructures can be tapered to
facilitate insertion into the subject, and can have different
cross-sectional shapes, for example depending on the intended use.
The microstructures typically have a rounded rectangular shape and
may include shape changes along a length of the microstructure. For
example, microstructures could include a shoulder that is
configured to abut against the stratum corneum to control a depth
of penetration and/or a shaft extending to the tip, with the shaft
being configured to control a position of the tip in the subject
and/or provide a surface for an electrode.
[0221] Other example shapes include circular, rectangular,
cruciform shapes, square, rounded square, rounded rectangular,
ellipsoidal, or the like, which can allow for increased surface
area, which is useful when coating microstructures to maximise the
coating volume and hence the amount of payload delivered per
microstructure, although it will be appreciated that a range of
other shapes could be used. Microstructures can have a rough or
smooth surface, or may include surface features, such as pores,
raised portions, serrations, or the like, which can increase
surface area and/or assist in penetrating or engaging tissue, to
thereby anchor the microstructures within the subject. This can
also assist in reducing biofouling, for example by prohibiting the
adherence and hence build-up of biofilms. The microstructures might
also be hollow or porous and can include an internal structure,
such as holes or similar, in which case the cross sectional shape
could also be at least partially hollow. In particular embodiments,
the microstructures are porous, which may increase the effective
surface area of the microstructure. The pores may be of any
suitable size to allow an analyte of interest to enter the pores,
but exclude one or more other analytes or substances, and thus,
will depend on the size of the analyte of interest. In some
embodiments, the pores may be less than about 10 .mu.m in diameter,
preferably less than about 1 .mu.m in diameter.
[0222] In one example, the microstructures have a rounded
rectangular shape when viewed in cross section through a plane
extending laterally through the microstructures and parallel to but
offset from the substrate. The microstructures may include shape
changes along a length of the microstructure. For example,
microstructures could include a shoulder that is configured to abut
against the stratum corneum to control a depth of penetration
and/or a shaft extending to the tip, with the shaft being
configured to control a position of the tip in the subject and/or
provide a surface for an electrode.
[0223] Different microstructures could be provided on a common
substrate, for example providing different shapes of microstructure
to achieve different functions. In one example, this could include
performing different types of measurement. In other examples,
microstructures could be provided on different substrates, for
example, allowing sensing to be performed via microstructures on
one patch and delivery of therapy to be performed via
microstructures on a different patch. In this example, this could
allow a therapy patch to be replaced once exhausted, whilst a
sensing patch could remain in situ. Additionally, measurements
could be performed between patches, for example, performing whole
of body impedance measurements between patches provided at
different locations on a subject.
[0224] Additionally and/or alternatively anchor microstructures
could be provided, which can be used to anchor the substrate to the
subject. In this regard, anchor microstructures would typically
have a greater length than that of the microstructures, which can
help retain the substrate in position on the subject and ensure
that the substrate does not move during the measurements or is not
being inadvertently removed. Anchor microstructures can include
anchoring structures, such as raised portions, which can assist
with engaging the tissue, and these could be formed by a shape of
the microstructure and/or a shape of a coating. Additionally, the
coating could include a hydrogel or other similar material, which
expands upon expose to moisture within the subject, thereby further
facilitating engagement with the subject. Similarly the
microstructure could undergo a shape change, such as swelling
either in response to exposure to substances, such as water or
moisture within the subject, or in response to an applied
stimulation. When applied to skin, the anchor microstructures can
enter the dermis, and hence are longer than other microstructures,
to help retain the substrate in place, although it will be
appreciated that this is not essential and will depend upon the
preferred implementation. In other examples the anchor
microstructures are rougher than other microstructures, have a
higher surface friction than other microstructures, are blunter
than other microstructures or are fatter than other
microstructures.
[0225] In a further example, at least part of the substrate could
be coated with an adhesive coating in order to allow the substrate
and hence patch, to adhere to the subject.
[0226] As previously mentioned, when applied to skin, the
microstructures typically enter the viable epidermis and in one
example, do not enter the dermis, although in other examples, may
enter the dermis. But this is not essential, and for some
applications, it may be necessary for the microstructures to enter
the dermis, for example projecting shortly through the viable
epidermis/dermis boundary or entering into the dermis a significant
distance, largely depending on the nature of the sensing being
performed. In one example, for skin, the microstructures have a
length that is at least one of less than 2500 .mu.m, less than 1000
.mu.m, less than 750 .mu.m, less than 600 .mu.m, less than 500
.mu.m, less than 400 .mu.m, less than 300 .mu.m, less than 250
.mu.m, greater than 100 .mu.m, greater than 50 .mu.m and greater
than 10 .mu.m, but it will be appreciated that other lengths could
be used. More generally, when applied to a functional barrier, the
microstructures typically have a length greater than the thickness
of the functional barrier, at least 10% greater than the thickness
of the functional barrier, at least 20% greater than the thickness
of the functional barrier, at least 50% greater than the thickness
of the functional barrier, at least 75% greater than the thickness
of the functional barrier and at least 100% greater than the
thickness of the functional barrier.
[0227] In another example, the microstructures have a length that
is no more than 2000% greater than the thickness of the functional
barrier, no more than 1000% greater than the thickness of the
functional barrier, no more than 500% greater than the thickness of
the functional barrier, no more than 100% greater than the
thickness of the functional barrier, no more than 75% greater than
the thickness of the functional barrier or no more than 50% greater
than the thickness of the functional barrier. This can avoid deep
penetration of underlying layers within the body, which can in turn
be undesirable, and it will be appreciated that the length of the
microstructures used will vary depending on the intended use, and
in particular the nature of the barrier to be breached, and/or
signals to be applied or measured. The length of the
microstructures can also be uneven, for example, allowing a blade
to be taller at one end than another, which can facilitate
penetration of the subject or functional barrier.
[0228] Similarly, the microstructures can have different widths
depending on the preferred implementation. Typically, the widths
are at least one of less than 25% of the length, less than 20% of
the length, less than 15% of the length, less than 10% of the
length, or less than 5% of the length. Thus, for example, when
applied to the skin, the microstructures could have a width of less
than 50 .mu.m, less than 40 .mu.m, less than 30 .mu.m, less than 20
.mu.m or less than 10 .mu.m. However, alternatively, the
microstructures could include blades, and could be wider than the
length of the microstructures. In some example, the microstructures
could have a width of less than 50000 .mu.m, less than 40000 .mu.m,
less than 30000 .mu.m, less than 20000 .mu.m, less than 10000
.mu.m, less than 5000 .mu.m, less than 2500 .mu.m, less than 1000
.mu.m, less than 500 .mu.m or less than 100 .mu.m. In blade
examples, it is also feasible to use microstructures having a width
substantially up to the width of the substrate.
[0229] In general the thickness of the microstructures is
significantly lower in order to facilitate penetration and is
typically less than 1000 .mu.m, less than 500 .mu.m, less than 200
.mu.m, less than 100 .mu.m, less than 50 .mu.m, less than 20 .mu.m,
less than 10 .mu.m, at least 1 .mu.m, at least 0.5 .mu.m or at
least 0.1 .mu.m. In general, the thickness of the microstructure is
governed by mechanical requirements, and in particular the need to
ensure the microstructure does not break, fracture or deform upon
penetration. However, this issue can be mitigated through the use
of a coating that adds additional mechanical strength to the
microstructures.
[0230] In one specific example, for epidermal sensing, the
microstructures have a length that is less than 300 .mu.m, greater
than 50 .mu.m, greater than 100 .mu.m and about 150 .mu.m, and, a
width that is greater than or about equal to a length of the
microstructure, and is typically less than 300 .mu.m, greater than
50 .mu.m and about 150 .mu.m. In another example, for dermal
sensing, the microstructures have a length that is less than 450
.mu.m, greater than 100 .mu.m, and about 250 .mu.m, and, a width
that is greater than or about equal to a length of the
microstructure, and at least of a similar order of magnitude to the
length, and is typically less than 450 .mu.m, greater than 100
.mu.m, and about 250 .mu.m. In other examples, longer
microstructures could be used, so for example for hyperdermal
sensing, the microstructures would be of a greater length. The
microstructures typically have a thickness that is less than the
width, significantly less than the width and of an order of
magnitude smaller than the width. In one example, the thickness is
less than 50 .mu.m, greater than 10 .mu.m, and about 25 .mu.m,
whilst the microstructure typically includes a flared base for
additional strength, and hence includes a base thickness proximate
the substrate that is about three times the thickness, and
typically is less than 150 .mu.m, greater than 30 .mu.m and about
75 .mu.m. The microstructures typically have a tip has a length
that is less than 50% of a length of the microstructure, at least
10% of a length of the microstructure and more typically about 30%
of a length of the microstructure. The tip further has a sharpness
that is at least 0.1 .mu.m, less than 5 .mu.m and typically about 1
.mu.m.
[0231] In one example, the microstructures have a relatively low
density, such as less than 10000 per cm.sup.2, such as less than
1000 per cm.sup.2, less than 500 per cm.sup.2, less than 100 per
cm.sup.2, less than 10 per cm.sup.2 or even less than 5 per
cm.sup.2. The use of relatively a low density facilitates
penetration of the microstructures through the stratum corneum and
in particular avoids the issues associated with penetration of the
skin by high density arrays, which in turn can lead to the need for
high powered actuators in order for the arrays to be correctly
applied. However, this is not essential, and higher density
microstructure arrangements could be used, including less than
50,000 microstructures per cm.sup.2, less than 30,000
microstructures per cm.sup.2, or the like. As a result, the
microstructures typically have a spacing that is less than 20 mm,
less than 10 mm, less than 1 mm, less than 0.1 mm or less than 10
.mu.m. It should be noted that in some circumstances,
microstructures are arranged in pairs, with the microstructures in
each pair having a small spacing, such as less than 10 .mu.m,
whilst the pairs have a great spacing, such as more than 1 mm, in
order to ensure a low overall density is maintained. However, it
will be appreciated that this is not essential, and higher
densities could be used in some circumstances.
[0232] In one specific example, the microstructures have a density
that is less than 5000 per cm.sup.2, greater than 100 per cm.sup.2,
and about 600 per cm.sup.2, leading to a spacing of less than 1 mm,
more than 10 .mu.m, and about 0.5 mm, 0.2 mm or 0.1 mm.
[0233] In this regard, it will be understood that the density,
shape and dimensions of the microstructures have an impact on the
ability of the microstructures to penetrate and/or pierce a barrier
such as the stratum corneum, so that changes in microstructure
density, shape or dimensions can alter the configuration of the
actuator required to ensure the microstructures penetrate or pierce
a barrier, such as the stratum corneum.
[0234] In one example, when optical sensing is performed, the
connections in the substrate include waveguides, or other
electromagnetically conductive paths, such as optical fibre, which
extend through the microstructures to one or more ports in the
microstructure, to allow electromagnetic radiation to be emitted
from or received via the ports. In one example, this is achieved by
having the microstructure made from, or contain, polymer, or
another similar material, which is at least partially transparent
to the frequency of electromagnetic radiation being applied or
received, which could include visible radiation, ultra-violet
radiation, infra-red radiation, or the like, depending on the
preferred application.
[0235] In one example, an at least partially electromagnetically
transparent core can be surrounded by an outer electromagnetically
opaque layer, with ports extending through the opaque layer, to
allow electromagnetic radiation to be emitted or received via the
ports. In this example, it will be appreciated that appropriate
positioning of the ports, allows radiation to be delivered or
received in a targeted manner, for example allowing this to be
directed into a particular depth within the viable epidermis, or
elsewhere. In one example, the transparent core could be made from
a waveguide, such as a fibre optic cable, or part thereof. For
example, the outer layer and/or reflective layer could be removed,
allowing the transparent core of the microstructure to be made of
the fibre optic core. In a further example, the microstructures
include electromagnetically reflective layers to allow
electromagnetic radiation to be conducted to and from designated
ports.
[0236] Similar arrangements could be provided for electrical
signalling, with the microstructures including an electrically
conductive core material and optionally including an electrically
insulating layer including ports to allow electrical signals to be
emitted from or received by the ports, again with ports optionally
being at different depths, to allow electrical signals to be
measured at different locations and/or depths.
[0237] Thus, the microstructure could include an electrically
conductive material covered by a non-conductive (insulating) layer,
with openings providing access to the conductive material to allow
conduction of electrical signals through the openings to thereby
define electrodes. In one example, the insulating layer extends
over part of a surface of the microstructure, including a proximal
end of the microstructure adjacent the substrate. The insulating
layer could extend over at least half of a length of the
microstructure and/or about 60 .mu.m, 90 .mu.m or 150 .mu.m of a
proximal end of the microstructure, and optionally, at least part
of a tip portion of the microstructure. In one specific example,
this is performed so the non-insulating portion is provided in the
epidermis and/or dermis, so stimulatory signals are applied to
and/or response signals received from, the epidermis and/or dermis.
The insulating layer could also extend over some or all of a
surface of the substrate. In this regard, in some examples
connections are formed on a surface of the substrate, in which case
a coating could be used to isolate these from the subject. For
example, electrical tracks on a surface of the substrate could be
used to provide electrical connections to the electrodes, with an
insulating layer being provided on top of the connections to ensure
the connections do not make electrical contact with the skin of the
subject, which could in turn adversely affect measured response
signals.
[0238] In another example, at least some of microstructures include
an electrode. The microstructures could be made from a metal or
other conductive material, so that the entire microstructure
constitutes the electrode, or alternatively the electrode could be
coated or deposited onto the microstructure, for example by
depositing a layer of gold to form the electrode. In a further
example, the microstructure could include an electrically
conductive core covered by a non-conductive layer, with openings
providing access to the core to allow conduction of electrical
signals through the openings. The electrode material could include
any one or more of gold, silver, colloidal silver, colloidal gold,
colloidal carbon, carbon nano materials, platinum, titanium,
stainless steel, or other metals, or any other biocompatible
conductive material.
[0239] The electrodes could be used to apply electrical signals to
a subject, measure intrinsic or extrinsic response electrical
signals, for example measuring ECG or impedances. In another
example, the one or more microstructure electrodes interact with
one or more analytes of interest such that a response signal is
dependent on a presence, absence, level or concentration of one or
more analytes of interest, thereby allowing the level or
concentration of one or more analytes to be quantified.
[0240] In one example, the microstructures include plates having a
substantially planar face having an electrode thereon. The use of a
plate shape maximizes the surface area of the electrode, whilst
minimizing the cross-sectional area of the microstructure, to
thereby assist with penetration of the microstructure into the
subject. This also allows the electrode to act as a capacitive
plate, allowing capacitive sensing to be performed. In one example,
the electrodes have a surface area of at least at least 10
mm.sup.2, at least 1 mm.sup.2, at least 100,000 .mu.m.sup.2, 10,000
.mu.m.sup.2, at least 7,500 .mu.m.sup.2, at least 5,000
.mu.m.sup.2, at least 2,000 .mu.m.sup.2, at least 1,000
.mu.m.sup.2, at least 500 .mu.m.sup.2, at least 100 .mu.m.sup.2, or
at least 10 .mu.m.sup.2. In one example, the electrodes have a
width or height that is up to 2500 .mu.m, at least 500 .mu.m, at
least 200 .mu.m, at least 100 .mu.m, at least 75 .mu.m, at least 50
.mu.m, at least 20 .mu.m, at least 10 .mu.m or at least 1 .mu.m. In
the case of electrodes provided on blades, the electrode width
could be less than 50000 .mu.m, less than 40000 .mu.m, less than
30000 .mu.m, less than 20000 .mu.m, less than 10000 .mu.m, or less
than 1000 .mu.m, as well as including widths outlined previously.
In this regard, it will be noted that these dimensions apply to
individual electrodes, and in some examples each microstructure
might include multiple electrodes.
[0241] In one specific example, the electrodes have a surface area
of less than 200,000 .mu.m.sup.2, at least 2,000 .mu.m.sup.2 and
about 22,500 .mu.m.sup.2, with the electrodes extending over a
length of a distal portion of the microstructure, optionally spaced
from the tip, and optionally positioned proximate a distal end of
the microstructure, again proximate the tip of the microstructure.
The electrode can extend over at least 25% and less than 50% of a
length of the microstructure, so that the electrode typically
extends over about 60 .mu.m 90 .mu.m or 150 .mu.m of the
microstructure and hence is positioned in a viable epidermis and/or
dermis of the subject in use.
[0242] In one example, at least some of the microstructures are
arranged in groups, such as pairs, with response signals or
stimulation being measured from or applied to the microstructures
within the group. The microstructures within the group can have a
specific configuration to allow particular measurements to be
performed. For example, when arranged in pairs, a separation
distance can be used to influence the nature of measurements
performed. For example, when performing bioimpedance measurements,
if the separation between the microstructures is greater than a few
millimetres, this will tend the measure properties of interstitial
fluid located between the electrodes, whereas if the distance
between the microstructures is reduced, measurements will be more
influenced by surface properties, such as the presence of materials
bound to the surface of the microstructures. Measurements are also
influenced by the nature of the applied stimulation, so that for
example, current at low frequencies will tend to flow though
extra-cellular fluids, whereas current at higher frequencies is
more influenced by intra-cellular fluids.
[0243] In one particular example, plate microstructures are
provided in pairs, with each pair including spaced apart plate
microstructures having substantially planar electrodes in
opposition. This can be used to generate a highly uniform field in
the subject in a region between the electrodes, and/or to perform
capacitive or conductivity sensing of substances between the
electrodes. However, this is not essential, and other
configurations, such as circumferentially spacing a plurality of
electrodes around a central electrode, can be used. Typically the
spacing between the electrodes in each group is typically less than
50 mm; less than 20 mm, less than 10 mm, less than 1 mm, less than
0.1 mm or less than 10 .mu.m, although it will be appreciated that
greater spacings could be used, including spacing up to dimensions
of the substrate and/or greater, if microstructures are distributed
across multiple substrates.
[0244] Thus, in one specific example, at least some of the
microstructures are arranged in pairs, with response signals being
measured between microstructures in the pair and/or stimulation
being applied between microstructures in the pair. Each pair of
microstructures typically includes spaced apart plate
microstructures having substantially planar electrodes in
opposition and/or spaced apart substantially parallel plate
microstructures.
[0245] In one example, at least some pairs of microstructures are
angularly offset, and in one particular example, are orthogonally
arranged. Thus, in the case of plate microstructures, at least some
pairs of microstructures extend in different and optionally
orthogonal directions. This distributes stresses associated with
insertion of the patch in different directions, and also acts to
reduce sideways slippage of the patch by ensuring plates at least
partially face a direction of any lateral force. Reducing slippage
either during or post insertion helps reduce discomfort, erythema,
or the like, and can assist in making the patch comfortable to wear
for prolonged periods. Additionally, this can also help to account
for any electrical anisotropy within the tissue, for example as a
result of fibrin structures within the skin, cellular anisotropy,
or the like.
[0246] In one specific example, adjacent pairs of microstructures
are angularly offset, and/or orthogonally arranged, and
additionally and/or alternatively, pairs of microstructures can be
arranged in rows, with the pairs of microstructures in one row are
orthogonally arranged or angularly offset relative to pairs of
microstructures in other rows.
[0247] In one specific example, when pairs of microstructures are
used, a spacing between the microstructures in each pair is
typically less than 0.25 mm, more than 10 .mu.m and about 0.1 mm,
whilst a spacing between groups of microstructures is typically
less than 1 mm, more than 0.2 mm and about 0.5 mm. Such an
arrangement helps ensure electrical signals are primarily applied
and measured within a pair and reduces cross talk between pairs,
allowing independent measurements to be recorded for each pair of
microstructures/electrodes.
[0248] To create an array of pairs of electrodes, this can be
performed by manufacturing a first substrate having first
microstructures and corresponding first apertures. An insulating
layer is then provided on a side of the first substrate opposite
the first microstructures before a second substrate is provided on
the insulating layer. In this example, the second substrate has
second microstructures extending through the insulating layer and
the first apertures to form pairs of first and second
microstructures, and an example of this will be described in more
detail below. In one example, the first and second apertures are
offset to reduce capacitive coupling between the first and second
substrates. Alternatively, other mechanisms for capacitive coupling
between the substrates could be used.
[0249] The microstructures can be configured in order to interact
with, and in particular, bind with one or more analytes of
interest, allowing these to be detected. Specifically, in one
example, binding of one or more analytes to the microstructures can
alter the charge carrying capability, in turn leading to changes in
capacitance of electrode pairs, which can then be monitored,
allowing analyte levels or concentrations to be derived. Binding of
analytes can be achieved using a variety of techniques, including
selection of mechanical properties of the microstructure, such as
the presence of pores or other physical structures, the material
from which the microstructures are manufactured, the use of
coatings, or otherwise influencing the microstructure properties,
such as by using magnetic microstructures.
[0250] Additionally, the microstructures and/or substrate can
incorporate one or more materials or other additives, either within
the body of the microstructure, or through addition of a coating
containing the additive. The nature of the material or additive
will vary depending on the preferred implementation and could
include a bioactive material, a reagent for reacting with analytes
in the subject, a binding agent for binding with analytes of
interest, a material for binding one or more analytes of interest,
a probe for selectively targeting analytes of interest, a material
to reduce biofouling, a material to attract at least one substance
to the microstructures, a material to repel or exclude at least one
substance from the microstructures, a material to attract at least
some analytes to the microstructures, or a material to repel or
exclude analytes. In this regard, substances could include any one
or more of cells, fluids, analytes, or the like. Example materials
include polyethylene, polyethylene glycol, polyethylene oxide,
zwitterions, peptides, hydrogels and self assembled monolayers.
[0251] The material can be contained within the microstructures
themselves, for example by impregnating the microstructures during
manufacture, can be the material from which the microstructures are
formed, or could be provided in a coating. Accordingly, it will be
appreciated that at least some of the microstructures can be coated
with a coating such as a material for binding one or more analytes
or interest, which can be used in order to target specific analytes
of interest, allowing these to bind or otherwise attach to the
microstructure, so that these can then be detected in situ using a
suitable detection mechanism, such as by detecting changes in
optical or electrical properties.
[0252] The analyte may be any compound able to be detected in the
epidermis and/or dermis. In particular embodiments, the analyte is
a marker of a condition, disease, disorder or a normal or
pathologic process that occurs in a subject, or a compound which
can be used to monitor levels of an administered substance in the
subject, such as a medicament (e.g., drug, vaccine), an illicit
substance (e.g. illicit drug), a non-illicit substance of abuse
(e.g. alcohol or prescription drug taken for non-medical reasons),
a poison or toxin, a chemical warfare agent (e.g. nerve agent, and
the like) or a metabolite thereof. Suitable analytes include, but
are not limited to a: [0253] nucleic acid, including DNA and RNA,
including short RNA species including microRNA, siRNA, snRNA, shRNA
and the like; [0254] antibody, or antigen-binding fragment thereof,
allergen, antigen or adjuvant; [0255] chemokine or cytokine; [0256]
hormone; [0257] parasite, bacteria, virus, or virus-like particle,
or a compound therefrom, such as a surface protein, an endotoxin,
and the like; [0258] epigenetic marker, such as the methylation
state of DNA, or a chromatin modification of a specific
gene/region; [0259] peptide; [0260] polysaccharide (glycan); [0261]
polypeptide; [0262] protein; and [0263] small molecule.
[0264] In particular embodiments, the analyte of interest is
selected from the group consisting of a nucleic acid, antibody,
peptide, polypeptide, protein and small molecule; especially a
polypeptide and protein; most especially a protein.
[0265] The analyte may be a biomarker, which is a biochemical
feature or facet that can be used to measure the progress of a
disease, disorder or condition or the effects of treatment of a
disease, disorder or condition. The biomarker may be, for example,
a virus or a compound therefrom, a bacterium or a compound
therefrom, a parasite or a compound therefrom, a cancer antigen, a
cardiac disease indicator, a stroke indicator, an Alzheimer's
disease indicator, an antibody, a mental health indicator, and the
like.
[0266] Alternatively, the analyte may be a compound which can be
used to monitor levels of an administered or ingested substance in
the subject, such as a medicament (e.g., drug, vaccine), an illicit
substance (e.g. illicit drug), a non-illicit substance of abuse
(e.g. alcohol or prescription drug taken for non-medical reasons),
a poison or toxin, a chemical warfare agent (e.g. nerve agent, and
the like) or a metabolite thereof.
[0267] In some embodiments, the analyte is a protein selected from
the group consisting of troponin or a subunit thereof, an enzyme
(e.g. amylase, creatinine kinase, lactate dehydrogenase,
angiotensin II converting enzyme), a hormone (e.g.
follicle-stimulating hormone or luteinising hormone), cystatin C,
C-reactive protein, TNF.alpha., IL-6, ICAM1, TLR2, TLR4, presepsin,
D-dimer, a viral protein (e.g. non-structural protein 1 (NS1)), a
bacterial protein, a parasitic protein (e.g. histone rich protein 2
(HRP2)), an antibody (e.g. an antibody produced in response to an
infection, such as a bacterial or viral infection including an
influenza infection) and botulinum toxin or a metabolite or subunit
thereof; especially troponin or a subunit thereof, amylase,
creatinine kinase, lactate dehydrogenase, angiotensin II converting
enzyme, follicle-stimulating hormone, luteinising hormone, cystatin
C, C-reactive protein, TNF.alpha., IL-6, ICAM1, TLR2, TLR4,
presepsin, D-dimer, botulinum toxin or a metabolite or subunit
thereof. In particular embodiments, the analyte is troponin or a
subunit thereof; especially troponin I, troponin C or troponin T;
most especially troponin I.
[0268] The analyte may be a small molecule, non-limiting examples
of which include a hormone (e.g. cortisol or testosterone),
neurotransmitter (e.g. dopamine), amino acid, creatinine, an
aminoglycoside (e.g. kanamycin, gentamicin and streptomycin), an
anticonvulsant (e.g. carbamazepine and clonazepam), an illicit
substance (e.g. methamphetamine, amphetamine,
3,4-methylenedioxymethamphetamine (MDMA), N-ethyl-3,4-methyl
enedioxyamphetamine (MDEA), 3,4-methylenedioxy-amphetamine (MDA),
cannabinoids (e.g. delta-9-tetrahydrocannabinol,
11-hydroxy-delta-9-tetrahydrocannabinol,
11-nor-9-carboxydelta-9-tetrahydrocannabinol), cocaine,
benzoylecgonine, ecgonine methyl ester, cocaethylene, ketamine, and
the opiates (e.g. heroin, 6-monoacetylmorphine, morphine, codeine,
methadone and dihydrocodeine), an anticoagulant (e.g. warfarin), a
chemical warfare agent, poison or toxin such as blister agents
(e.g. cantharidin, furanocoumarin, sulfur mustards (e.g.
1,2-bis(2-chloroethylthio)ethane,
1,3-bis(2-chloroethylthio)-n-propane,
1,4-bis(2-chloroethylthio)-n-butane,
1,5-bis(2-chloroethylthio)-n-pentane,
2-chloroethylchloromethylsulfide, bis(2-chloroethyl)sulfide,
bis(2-chloroethylthio)methane, bis(2-chloroethylthiomethyl)ether,
bis(2-chloroethylthioethyl)ether), nitrogen mustards (e.g.
bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine and
tris(2-chloroethyl)amine) and phosgene oxime), arsenicals (e.g.
ethyldichloroarsine, methyldichloroarsine, phenyldichloroarsine and
2-chlorovinyldichloroarsine) and urticants e.g. phosgene oxime),
blood agents (e.g. cyanogen chloride, hydrogen cyanide and arsine),
choking agents (e.g. chlorine, chloropicrin, diphosgene and
phosgene), nerve agents (e.g. tabun, sarin, soman, cyclosarin,
novichok agents,
2-(dimethylamino)ethyl-N,N-dimethylphosphoramidofluoridate (GV),
(S)-(ethyl{[2-(diethylamino)ethyl]sulfanyl}(ethyl)phosphinate)
(VE), O,O-diethyl-S-[2-(diethylamino)ethyl]phosphorothioate (VG),
S-[2-(diethylamino)ethyl]-O-ethyl methylphosphonothioate (VM),
ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate
(VX), tetrodotoxin and saxitoxin), animal venom component (e.g.
tetrodotoxin and saxitoxin), cyanide, arsenic, a tropane alkaloid
(e.g. atropine, scopolamine and hyoscyamine), a piperidine alkaloid
(e.g. coniine, N-methylconiine, conhydrine, pseudoconhydrine and
gamma-coniceine), a curare alkaloid (e.g. tubocurarine), nicotine,
caffeine, quinine, strychnine, brucine, aflatoxin), and the like or
a metabolite thereof. In some embodiments the small molecule is
selected from the group consisting of cortisol, testosterone,
creatinine, dopamine, kanamycin, gentamicin, streptomycin,
carbamazepine, clonazepam, methamphetamine, amphetamine, MDMA,
MDEA, MDA, delta-9-tetrahydrocannabinol,
11-hydroxy-delta-9-tetrahydrocannabinol,
11-nor-9-carboxydelta-9-tetrahydrocannabinol, cocaine,
benzoylecgonine, ecgonine methyl ester, cocaethylene, ketamine,
heroin, 6-monoacetylmorphine, morphine, codeine, methadone,
dihydrocodeine, warfarin, cantharidin, furanocoumarin,
1,2-bis(2-chloroethylthio)ethane,
1,3-bis(2-chloroethylthio)-n-propane,
1,4-bis(2-chloroethylthio)-n-butane,
1,5-bis(2-chloroethylthio)-n-pentane,
2-chloroethylchloromethylsulfide, bis(2-chloroethyl)sulfide,
bis(2-chloroethylthio)methane, bis(2-chloroethylthiomethyl)ether,
bis(2-chloroethylthioethyl)ether), bis(2-chloroethyl)ethylamine,
bis(2-chloroethyl)methylamine and tris(2-chloroethyl)amine),
phosgene oxime, ethyldichloroarsine, methyldichloroarsine,
phenyldichloroarsine, 2-chlorovinyldichloroarsine, phosgene oxime,
cyanogen chloride, hydrogen cyanide, arsine, chlorine,
chloropicrin, diphosgene, phosgene, tabun, sarin, soman,
cyclosarin, novichok agents,
2-(dimethylamino)ethyl-N,N-dimethylphosphoramidofluoridate (GV),
(S)-(ethyl{[2-(diethylamino)ethyl]sulfanyl}(ethyl)phosphinate)
(VE), O,O-diethyl-S-[2-(diethylamino)ethyl]phosphorothioate (VG),
S-[2-(diethylamino)ethyl]-O-ethyl methylphosphonothioate (VM),
ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate
(VX), tetrodotoxin, saxitoxin, cyanide, arsenic, atropine,
scopolamine, hyoscyamine, coniine, N-methylconiine, conhydrine,
pseudoconhydrine, gamma-coniceine, tubocurarine, nicotine,
caffeine, quinine, strychnine, brucine, aflatoxin and metabolites
thereof.
[0269] In some embodiments, the analyte is a peptide, non-limiting
examples of which include a hormone (e.g. oxytocin,
gonadotropin-releasing hormone and adrenocorticotropic hormone),
B-type natriuretic peptide, N-terminal pro B-type natriuretic
peptide (NT-proBNP) and an animal venom component (e.g. a peptidic
component of spider, snake, scorpion, bee, wasp, ant, tick,
conesnail, octopus, fish (e.g stonefish) and jellyfish venom) or a
metabolite thereof. In particular embodiments, the peptide is
oxytocin, gonadotropin-releasing hormone, adrenocorticotropic
hormone, B-type natriuretic peptide or NT-proBNP.
[0270] In some embodiments, the analyte is a polysaccharide
(glycan), suitable non-limiting examples of which include inulin,
endotoxins (lipopolysaccharides), anticoagulants (e.g. heparin) and
metabolites thereof.
[0271] In some embodiments, the analyte is an illicit substance or
a non-illicit substance of abuse or a metabolite thereof. Suitable
illicit substances include, but are not limited to,
methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine
(MDMA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA),
3,4-methylenedioxy-amphetamine (MDA), cannabinoids (e.g.
delta-9-tetrahydrocannabinol,
11-hydroxy-delta-9-tetrahydrocannabinol,
11-nor-9-carboxydelta-9-tetrahydrocannabinol), cocaine,
benzoylecgonine, ecgonine methyl ester, cocaethylene, ketamine, and
the opiates (e.g. heroin, 6-monoacetylmorphine, morphine, codeine,
methadone and dihydrocodeine), or metabolites thereof. Non-limiting
non-illicit substances of abuse include alcohol, nicotine,
prescription medicine or over the counter medicine taken for
non-medical reasons, a substance taken for a medical effect,
wherein the consumption has become excessive or inappropriate (e.g.
pain medications such as opiates, sleep aids, anti-anxiety
medication, methylphenidate, erectile-dysfunction medications), and
the like, or metabolites thereof.
[0272] In some embodiments, the analyte is a medicament or a
component or metabolite thereof. A wide variety of medicaments are
suitable analytes, including, but not limited to, cancer therapies,
vaccines, analgesics, antipsychotics, antibiotics, anticoagulants,
antidepressants, antivirals, sedatives, anti diabetics,
contraceptives, immunosuppressants, antifungals, antihelmintics,
stimulants, biological response modifiers, non-steroidal
anti-inflammatory drugs (NSAIDs), corticosteroids,
disease-modifying anti-rheumatic drugs (DMARDs), anabolic steroids,
antacids, antiarrhythmics, thrombolytics, anticonvulsants,
antidiarrheals, antiemetics, antihistamines, antihypertensives,
anti-inflammatories, antineoplastics, antipyretics, barbiturates,
.beta.-blockers, bronchodilators, cough suppressants, cytotoxics,
decongestants, diuretics, expectorants, hormones, laxatives, muscle
relaxants, vasodilators, sedatives, vitamins, and metabolites
thereof. Various examples of these medicaments are described herein
and are well known in the art.
[0273] In some embodiments, the analyte is a poison, toxin,
chemical warfare agent, or metabolite thereof. Suitable poisons,
toxins and chemical warfare agents include, but are not limited to,
including blister agents (e.g. cantharidin, furanocoumarin, sulfur
mustards (e.g. 1,2-bis(2-chloroethylthio)ethane,
1,3-bis(2-chloroethylthio)-n-propane,
1,4-bis(2-chloroethylthio)-n-butane,
1,5-bis(2-chloroethylthio)-n-pentane,
2-chloroethylchloromethylsulfide, bis(2-chloroethyl) sulfide,
bis(2-chloroethylthio)methane, bis(2-chloroethylthiomethyl)ether,
bis(2-chloroethylthioethyl)ether), nitrogen mustards (e.g.
bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine and
tris(2-chloroethyl)amine) and phosgene oxime), arsenicals (e.g.
ethyldichloroarsine, methyldichloroarsine, phenyldichloroarsine and
2-chlorovinyldichloroarsine) and urticants e.g. phosgene oxime),
blood agents (e.g. cyanogen chloride, hydrogen cyanide and arsine),
choking agents (e.g. chlorine, chloropicrin, diphosgene and
phosgene), nerve agents (e.g. tabun, sarin, soman, cyclosarin,
novichok agents,
2-(dimethylamino)ethyl-N,N-dimethylphosphoramidofluoridate (GV),
(S)-(ethyl{[2-(diethylamino)ethyl]sulfanyl}(ethyl)phosphinate)
(VE), O,O-diethyl-S-[2-(diethylamino)ethyl]phosphorothioate (VG),
S-[2-(diethylamino)ethyl]-O-ethyl methylphosphonothioate (VM),
ethyl(2-[bis(propan-2-yl)amino]ethyl sulfanyl)(methyl)phosphinate
(VX), tetrodotoxin, saxitoxin and botulinum toxin), animal venom
component (e.g. tetrodotoxin, saxitoxin or other component of
spider, snake, scorpion, bee, wasp, ant, tick, conesnail, octopus,
fish (e.g stonefish) and jellyfish venom), cyanide, arsenic, a
component of Atropa Belladonna (deadly nightshade) such as a
tropane alkaloid (e.g. atropine, scopolamine and hyoscyamine), a
component of hemlock such as a piperidine alkaloid (e.g. coniine,
N-methylconiine, conhydrine, pseudoconhydrine and gamma-coniceine),
a curare alkaloid (e.g. tubocurarine), nicotine, caffeine, alcohol,
quinine, atropine, strychnine, brucine, aflatoxin and metabolites
thereof. In some embodiments, the analyte is a chemical warfare
agent such as a blister agent (e.g. cantharidin, furanocoumarin, a
sulfur mustard (e.g. 1,2-bis(2-chloroethylthio)ethane,
1,3-bis(2-chloroethylthio)-n-propane,
1,4-bis(2-chloroethylthio)-n-butane,
1,5-bis(2-chloroethylthio)-n-pentane,
2-chloroethylchloromethylsulfide, bis(2-chloroethyl)sulfide,
bis(2-chloroethylthio)methane, bis(2-chloroethylthiomethyl)ether or
bis(2-chloroethylthioethyl)ether), a nitrogen mustard (e.g.
bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine or
tris(2-chloroethyl)amine) or phosgene oxime), an arsenical (e.g.
ethyldichloroarsine, methyldichloroarsine, phenyldichloroarsine or
2-chlorovinyldichloroarsine) or an urticant e.g. phosgene oxime), a
blood agent (e.g. cyanogen chloride, hydrogen cyanide or arsine), a
choking agent (e.g. chlorine, chloropicrin, diphosgene or
phosgene), a nerve agent (e.g. tabun, sarin, soman, cyclosarin, a
novichok agent,
2-(dimethylamino)ethyl-N,N-dimethylphosphoramidofluoridate (GV),
(S)-(ethyl {[2-(diethylamino)ethyl]sulfanyl}(ethyl)phosphinate)
(VE), O,O-diethyl-S-[2-(diethylamino)ethyl]phosphorothioate (VG),
S-[2-(diethylamino)ethyl]-O-ethyl methylphosphonothioate (VM),
ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate
(VX), tetrodotoxin, saxitoxin or botulinum toxin) or a metabolite
thereof.
[0274] Examples of suitable analytes, diseases, disorders or
conditions, or applications for which they are relevant and known
lowest clinically relevant serum concentration ranges are provided
in Table 1.
TABLE-US-00001 TABLE 1 Lowest clinically Relevant disease, relevant
disorder or concentration condition, or (where Molecular Analyte
application available) weight Troponin or a subunit thereof,
Cardiac damage, Less than 30 23 kDa, 18 kDa such as troponin I,
troponin C or myocardial ng/L and 34 kDa, troponin T infarction,
acute respectively for coronary syndrome I, C and T subunits
Cortisol (serum) Addison's disease, Less than 650 362 Da Cushing's
disease, nmol/L adrenal and/or pituitary gland function,
psychological stress (wellness applications) Creatinine Renal
failure, Less than 100 113 Da creatinine clearance .mu.mol/L
estimates Dopamine Parkinson's disease, 0-30 pg/mL 153 Da brain
cancers, depression Aminoglycosides (e.g. Monitor dose of 5-10 mg/L
Varied ~300- kanamycin, gentamicin, therapeutic for 600 Da
streptomycin) bacterial infection Anticonvulsants (e.g. Monitor
dose of 0.02-12 mg/L Varied ~100 Da carbamazepine and clonazepam)
therapeutic for epilepsy Hormones such as follicle Assisted
fertility, Varied Varied ~200- stimulating hormone, luteinising
calcium levels, 300 Da hormone, oxytocin, gonadotropin- substance
abuse releasing hormone and (doping) testosterone Amylase
Pancreatitis, bile Less than 100 50 kDa duct obstruction U/L
Creatinine kinase Skeletal muscle Less than 200 80 kDa damage,
which may U/L be indicative of rhabdomyolysis, injury and/or drug
side-effects (statins) Lactate dehydrogenase Hepatic damage 119-229
U/L 140 kDa B-type natriuretic peptide (BNP) Cardiac failure 100
ng/L 36 kDa (high molecular weight form) or 3.5 kDa (low molecular
weight form) NT-proBNP Cardiac failure 300 ng/L 8.5 kDa Angiotensin
II converting enzyme Essential 8-100 U/L 60-170 kDa hypertension
Cystatin C Renal failure 0.6-1 mg/L 13 kDa Stress hormones e.g.
Adrenal 2-11 pmol/L ~4 kDa adrenocorticotropic hormone
insufficiency or (ACTH) overactivity Inflammatory markers (e.g. C-
Bacterial or viral Less than 10 Varied 120 kDa reactive protein
(CRP), TNF.alpha., IL- infection, mg/L (CRP) (CRP) 6, ICAM1, TLR2,
TLR4, autoimmune presepsin) disorders, rheumatological disorders,
sepsis Inulin Renal failure, Varied Varied creatinine clearance
(dependent on estimates amount administered) Illicit substances
(e.g. Drug abuse, Varied Varied ~200- methamphetamine, amphetamine,
compliance (dependent on 300 Da 3,4- monitoring, application e.g.
methylenedioxymethamphetamine rehabilitation, rehabilitation
(MDMA), N-ethyl-3,4- screening compared with
methylenedioxyamphetamine screening or (MDEA), 3,4-methylenedioxy-
drug abuse, amphetamine (MDA), and identity of cannabinoids (e.g.
delta-9- substance) tetrahydrocannabinol, 11-hydroxy-delta-9-
tetrahydrocannabinol, 11-nor-9-carboxydelta-9-
tetrahydrocannabinol), cocaine, benzoylecgonine, ecgonine methyl
ester, cocaethylene, ketamine, and the opiates (e.g. heroin,
6-monoacetylmorphine, morphine, codeine, methadone and
dihydrocodeine)) Anticoagulants (e.g. warfarin and Monitor dose of
Varied Varied heparin) therapeutic for blood clotting disorders and
diseases Glycoproteins and glycans Bacterial infection Varied
Varied ~10-20 (i.e. bacterial kDa endotoxins) Cellular components
and Bacterial infection, Varied Varied breakdown products exosome
detection, cancer, platelet detection D-dimer Pulmonary 0.4 mg/mL
180 kDa embolism Oligonucleotides and Bacterial infection, Varied
Varied ~200- polynucleotides (e.g. DNA, RNA viral infection, 300 Da
and fragments thereof) circulating tumour cell breakdown, solid
tissue cancers Chemical warfare agents (e.g. Chemical warfare,
Varied Varied blister agents, blood agents, environmental choking
agents and nerve agents) contamination
[0275] In some embodiments, the analyte is a metabolite of any one
of the above exemplary analytes.
[0276] While the analyte preferably binds directly to the binding
agent, the invention also contemplates detecting agents probative
of the analyte of interest such as a specific binding pair member
complementary to the analyte of interest, whose presence will be
detected only when a particular analyte of interest is present in a
sample. Thus, the agent probative of the analyte becomes the
analyte that is detected.
[0277] In some embodiments, the microstructures are coated with a
material that reduces absorption of analytes that are not of
interest. Example materials include alkyl groups coated with BSA
(bovine serum albumin), bifunctional polyethylene glycol (PEG)
polymers, or the like. Such materials have the effect of reducing
adsorption of non-specific analytes, which are effectively repelled
from the microstructures.
[0278] It will be appreciated that multiple coatings could be used
in conjunction, for example, to repel or exclude non-specific
analytes and bind analytes of interest, thereby allowing specific
analytes of interest to be selectively captured, whilst
non-specific analytes remain uncaptured.
[0279] A polymer coating, including a molecularly imprinted polymer
coating, may be applied using a variety of techniques routinely
used in the art. For example, the microstructures can be coated
with a polymer using a variety of techniques, including dip
coating, spray coating, deposition coating, electropolymerisation,
drop casting, electrospinning, ink jet coating, spin coating, or
the like; especially electropolymerisation. In one example, a
coating solution is applied to the microstructures and allowed to
dry in situ, optionally using a gas jet. Where the coating is a
polymer coating, the polymer may, in some embodiments, be
synthesised prior to coating using, for example, bulk
polymerisation. In alternative embodiments, the polymer is
synthesised and coated simultaneously, such as when synthesising
and coating using electropolymerisation. A skilled person will be
well aware of suitable techniques.
[0280] Molecularly imprinted polymers may be prepared using a
variety of techniques, non-limiting examples of which include bulk
polymerisation and electropolymerisation in the presence of a
template (i.e. the one or more analytes of interest or a fragment
or subunit thereof); especially electropolymerisation.
[0281] For example, a molecularly imprinted polymer may be prepared
by (a) preparing a polymerisation solution comprising one or more
monomers of interest and a solvent (e.g. phosphate-buffered
saline); (b) adding one or more template compounds (e.g. one or
more analytes of interest or a fragment or subunit thereof) to the
prepared polymerisation solution; (c) polymerising the
template/polymerisation solution to form a molecularly imprinted
polymer, optionally in the presence of one or more additives (e.g.
dopant, redox moiety etc.); and (d) separating the molecularly
imprinted polymer from the one or more template compounds.
Molecularly imprinted polymer properties may be optimised using
techniques routine in the art, such as varying the concentration of
the one or more monomers and/or template compounds.
[0282] The polymer may be coated in any form suitable for detecting
the one or more analytes of interest, such as a film, particle,
fibre or nanotube; especially a film.
[0283] The coating may be of a suitable thickness for determining
analyte presence, absence, level or concentration, such as, but not
limited to, 1 nm to 100 nm; especially 10 nm to 20 nm, most
especially about 15 nm.
[0284] While the polymer coating may be the only coating applied to
the electrode, in some embodiments it may be desirable to increase
the binding (adhesion) of the polymer coating to the electrode.
Accordingly, in such embodiments, an agent which increases binding
of the polymer coating to the electrode may be applied prior to
adding the coating. Suitable agents include, but are not limited
to, organosilanes, silicones, siloxanes, amide and amine containing
compounds, organophosphorus compounds, self-assembled monolayers or
other coupling agents.
[0285] To optimise coating, properties of the coating can be
controlled through the addition of one or more other agents such as
a viscosity enhancer, a detergent or other surfactant, and an
adjuvant. These ingredients can be provided in a range of different
concentrations. For example, the viscosity enhancer or surfactant
can form between 0% and 90% of the coating solution.
[0286] A range of different viscosity enhancers can be used and
examples include methylcellulose, carboxymethylcellulose (CMC),
gelatin, agar, and agarose and any other viscosity modifying
agents. The solution typically has a viscosity of between 10.sup.-3
Pas and 10.sup.-1 Pas. In one example, using a coating solution
containing 1-2% methylcellulose, which results in suitable uniform
coatings, resulting in a viscosity within the range 0.011
(1%)-0.055 (2%) Pas.
[0287] Similarly, a range of different surfactants can be used to
modify the surface tension of the coating solution, such as any
detergent or any suitable agent that decreases surface tension, and
that is biocompatible at a low concentration. The solution
properties are also typically controlled through the addition of
one or more other agents such as a viscosity enhancer, a detergent,
other surfactant, or anything other suitable material. These
ingredients can be provided in a range of different concentrations.
For example, the viscosity enhancer or surfactant can form between
0% and 90% of the coating solution.
[0288] As an alternative to using a coating technique, reagents can
alternatively be embedded within the microstructures. Thus, for
example, in the case of moulded patches manufactured using a
polymer material, the reagent can be introduced into the mould
together with the polymer material so that the reagent is
distributed throughout the structures. In this example, the polymer
can be arranged so that pores form within the structures during the
curing process.
[0289] Using affinity surface coatings on each structure also
allows a reduction of non-specific adsorption of ISF and/or blood
components whilst facilitating specific extraction of the molecular
targets of interest.
[0290] Thus, in one example, the one or more microstructures
interact with one or more analytes of interest such that a response
signal is dependent on a presence, absence, level or concentration
of analytes of interest. In one particular example, the analytes
interact with a coating on the microstructures to change electrical
and/or optical properties of the coating, thereby allowing the
analytes to be detected.
[0291] For example, measurements can be performed by passing a
current between electrodes, with measurements of the resulting
signal between the electrodes being used to detect changes in the
electrical properties and hence, the presence, absence, level or
concentration of analytes. In this regard, the electrical output
signal can be indicative of any one or more of a voltage, a
current, a resistance, a capacitance, a conductance, or an
impedance, or a change in any of these variables. Thus, signals
could be potentiometric, amperometric, voltametric, impedimetric,
or the like.
[0292] For example, impedance measurements, such as in
electrochemical impedance spectroscopy (EIS), investigate the
dynamics of the bound analyte or the charge transfer in the bulk or
the interfacial region of the MIP and/or aptamer. In this regard,
when an MIP (especially a conductive MIP) captures a target
analyte, the MIP cavities are filled, hindering the diffusion of
ions in the bulk polymer. In addition, captured analyte can strain
the structure of the conductive MIP causing increase in the charge
transfer in the polymer. Similarly when an aptamer captures a
target analyte, the captured analyte can change the structure of
the aptamer changing the electrical properties. The measurement
only requires ions in the samples and can be done without a redox
moiety.
[0293] In this example, the electrodes can be arranged in pairs,
although alternatively the system could measure impedances between
different groups of electrodes, for example with one group acting
as a working electrode and the other group working as a counter
electrode.
[0294] In a further example, voltametric/amperometric techniques
can be used, including cyclic voltammetry (CV), liner sweep
voltammetry (LSV), differential pulse voltammetry (DPV), square
wave voltammetry (SWV), and chronoamperometry (CA).
[0295] In this example, a current output is generated from the
redox reaction of the electroactive species (redox moiety) which
takes place on the conductive material (e.g gold microstructures).
When analyte of interest is captured in the MIP (especially
insulating MIP coating), the MIP cavities are filled thereby
blocking/hindering the diffusion of the redox moieties towards the
gold surface. Decrease in the penetration of the analyte in the
results to decrease in the current output. Similarly when an
analyte of interest is captured in the aptamer, the structure of
the aptamer changes resulting in the redox moieties moving relative
to the microstructure surface, thereby altering the current
output.
[0296] Since redox a reaction is required in this type of
transduction, some researchers incorporate a redox moiety in the
polymeric matrix.
[0297] In this example, reference electrodes might also be
provided, in which case electrodes might be arranged in three
groups, including working, counter and reference electrodes. The
reference electrodes need only be in the vicinity of the working
and counter electrodes, so that, for example, electrodes could be
arranged in pairs of working and counter electrodes, with a row of
pairs of electrodes being used as reference electrodes.
[0298] In a further example potentiometric measurements can be
performed in which an electrical output is generated in response to
binding of target analyte in the MIP and/or aptamer. Here the
change in the voltage corresponding to the amount of analyte bound
in the MIP and/or aptamer is measured. Potentiometric techniques
can be found in sensor like ion selective electrodes (ISE) and
field-effect transistors (FET).
[0299] Other measurement techniques include mass sensitive acoustic
transducers such as surface-acoustic wave (SAW) oscillator,
Love-wave oscillator, or quartz crystal microbalance. (QCM). In
binding of analyte could be quantified via the change in the
oscillation frequency resulting from the mass change at the
oscillator surface.
[0300] In a further example, one or more microstructures include a
treatment material, and wherein at least one treatment delivery
mechanism is provided that controls release of the treatment
material. In one preferred example, release of the treatment
material is controlled by applying stimulation to the
microstructure(s), for example by applying light, heat or
electrical stimulation to release the treatment material.
[0301] In one preferred example, the treatment material is
contained in a coating on the at least one microstructure and the
stimulation is used to dissolve the coating on the microstructure
and thereby deliver the treatment material. It will be appreciated
that this technique can be applied to any treatment material that
can be incorporated into a coating, and which can be selectively
released using stimulation, such as mechanical, magnetic, thermal,
electrical, electromagnetic or optical stimulation.
[0302] The nature of the treatment material will vary depending on
the preferred implementation and/or the nature of the treatment
being performed, including whether the treatment is cosmetic or
therapeutic. Example treatment materials include, but are not
limited to, nanoparticles, a nucleic acid, an antigen or allergen,
parasites, bacteria, viruses, or virus-like particles, metals or
metallic compounds, molecules, elements or compounds, DNA, protein,
RNA, siRNA, sfRNA, iRNA, synthetic biological materials, polymers,
drugs, or the like.
[0303] It will be appreciated that the use of coatings is not
essential however, and additionally and/or alternatively treatment
materials can be incorporated into the microstructures
themselves.
[0304] Irrespective of how treatment materials are provided, the
substrate can include a plurality of microstructures with different
microstructures having different treatment materials and/or
different treatment doses. In this case, the processing devices can
control the therapy delivery mechanism to release treatment
material from selected microstructures, thereby allowing different
treatments to be administered, and/or allowing differential dosing,
depending on the results of measurements performed on the subject.
In particular, as will be described in more detail below, the
processing devices typically perform an analysis at least in part
using the measured response signals; and, use results of the
analysis to control the at least one therapy delivery mechanism,
thereby allowing personalised treatment to be administered
substantially in real time.
[0305] It will be appreciated that microstructures could be
differentially coated, for example by coating different
microstructures with different coatings, and/or by coating
different parts of the microstructures with different coatings.
This could be used to allow different analytes to be detected at
different depths, so that for example a different coating is used
for part of the microstructure that enters the dermis as opposed to
the viable epidermis. This could also be used to allow for
detection of different analytes, or different levels or
concentrations of the same analyte. Additionally, at least some
microstructures could remain uncoated, for example, to allow these
to be used as a control, some may be partially coated, or may
include a porous structure with an internal coating. It will also
be appreciated that multiple coatings could be provided. For
example, an outer coating could be provided that gives mechanical
strength during insertion, and which dissolves once in-situ,
allowing an underlying functional coating to be exposed, for
example to allow analytes to be detected.
[0306] The nature of the coating and the manner in which this is
applied will vary depending on the preferred implementation and
techniques such as dip coating, spray coating, jet coating or the
like, could be used, as described above. The thickness of the
coating will also vary depending on the circumstances and the
intend functionality provided by the coating. For example, if the
coating is used to provide mechanical strength, or contains a
payload material to be delivered to the subject, a thicker coating
could be used, whereas if the coating is used for sensing other
applications, a thinner coating might be required.
[0307] In one example, stimulation, such as chemical, biochemical,
electrical, optical or mechanical stimulation, can be used to
release material from the coating on the microstructure, disrupt
the coating, dissolve the coating or otherwise release the
coating.
[0308] In another example, the microstructures can be coated with a
selectively dissolvable coating. The coating could be adapted to
dissolve after a defined time period, such as after the
microstructures have been present within the subject for a set
length of time, in response to the presence, absence, level or
concentration of one or more analytes in the subject, upon
breaching or penetration of the functional barrier, or in response
application of a stimulatory signal, such as an electrical signal,
optical signal or the like. Dissolving of the coating can be used
in order to trigger a measurement process, for example by exposing
a binding agent, or other functional feature, so that analytes are
only detected once the coating has dissolved.
[0309] In a further example, dissolving of the coating could be
detected, for example through a change in optical or electrical
properties, with the measurement being performed after the coating
has dissolved. Thus, dissolving of the coating could be detected
based on a change in a response signal.
[0310] In one example, the coating can be used to provide
mechanical properties. For example, the coating can provide a
physical structure that can be used to facilitate penetration of
the barrier, for example by providing a microstructure with a
smooth tapered outer profile. The coating can strengthen the
microstructures, to prevent microstructures breaking, fracturing,
buckling or otherwise being damaged during insertion, or could be
used to help anchor the microstructures in the subject. For
example, the coating could include hydrogels, which expand upon
exposure to moisture, so that the size of the microstructure and
coating increases upon insertion into the subject, thereby it
harder to remove the microstructure.
[0311] The coating can also be used to modify surface properties of
the microstructures, for example to increase or decrease
hydrophilicity, increase or decrease hydrophobicity and/or minimize
biofouling. The coating can also be used to attract, repel or
exclude at least one substance, such as analytes, cells, fluids, or
the like. The coating could also dissolve to expose a
microstructure, a further coating or material, allowing this to be
used to control the detection process. For example, a time release
coating could be used to enable a measurement to be performed a set
time after the patch has been applied. This could also be used to
provide stimulation to the subject, for example by releasing a
treatment or therapeutic material, or the like.
[0312] Thus, in one example, the system includes a plurality of
microstructures and wherein different microstructures are
differentially responsive to analytes. For example, different
microstructures could be responsive to different analytes,
responsive to different combination of analytes, responsive to
different levels or concentrations of analytes, or the like.
[0313] In one example, at least some of the microstructures attract
at least one substance to the microstructures and/or repel or
exclude at least one substance from the microstructures. The nature
of the substance will vary depending on the preferred
implementation and may include one or more analytes, or may include
other substances containing analytes, such as ISF, blood or the
like. This can be used to attract, repel or exclude analytes, for
example attracting analytes of interest, allowing these to be
concentrated and/or sensed, or repelling or excluding analytes that
are not of interest.
[0314] The ability to repel or exclude substances can also assist
with preventing biofouling. For example, the microstructures could
contain a material, or include a coating, such as polyethylene
glycol (PEG), which generally repels substances from the surface of
the microstructure. Reduction in biofouling could also be achieved
based on a choice of microstructure material or structure of the
microstructure e.g. coating the binding agent in the pores of a
porous microstructure, surface coatings that release to expose a
sensing surface when sensing is to be performed, permeable coatings
such as a porous polymer e.g. a nylon membrane, a
polyvinylidenefluoride coating, a polyphenylenediamine coating, a
polyethersulfone coating, or a hydrogel coating such as a
poly(hydroxyethyl methacrylate) or PEG coating; an isoporous silica
micelle membrane; a protein membrane, such as a fibroin membrane; a
polysaccharide membrane, such as a cellulose membrane or a chitosan
membrane; or a diol or silane membrane; releasable coatings that
interfere with biofouling material; and/or porous coatings. In
particular embodiments, the microstructure is porous, and the
binding agent is coated in the pores of the microstructure.
[0315] In another example, biofouling can be accounted for using a
control. For example, a patch could include functionalised
microstructures for analyte detection as well as un-functionalised
microstructures that act as a control. Assuming both sets of
microstructures are subject to similar levels of biofouling,
changes in response signals measured via the un-functionalised
microstructures can be used to quantify a degree of biofouling that
has occurred. This can then be accounted for when processing
signals from the functionalised microstructures, for example by
removing any change in response signals arising from the
biofouling.
[0316] As described above, the system includes an actuator
configured to apply force to the substrate, which in one example is
used to help the microstructures to breach the barrier. The
actuator could additionally and/or alternatively be used for other
purposes.
[0317] For example, movement of the microstructures could be used
to sense tissue mechanical properties. In this example, a response
of the actuator, such as an amount of current required to induce
movement of the microstructures, could be used to sense mechanical
properties, such as a degree of elasticity, or the like, which can
in turn be indicative of health issues, such as diseases or
similar. This could also be used in conjunction with mechanical
response signals, for example measuring a stress or strain on the
microstructures using a suitable sensing modality, allowing the
transmission of actuator movements to be monitored. Other external
mechanical stimulus could also be used, such providing a ring or
other structure around the patch, which generates pressure waves
within the tissue, allowing the responses to be measured.
[0318] The actuator can be used to provide mechanical stimulation,
for example to trigger a biological response, such as inflammation,
or to attract or repel substances. Additionally, physical movement
can be used to release material from a coating on at least some
microstructures, or could be used to disrupt, dissolve, dislodge or
otherwise release a coating on at least some microstructures. This
can be used to trigger a measurement process, for example,
releasing a coating or material to trigger a reaction with
analytes, allowing the analytes to be detected.
[0319] The actuator can also be used to cause the microstructures
to penetrate the barrier, or retract the microstructures from the
barrier and/or the subject. In one example, this allows the
microstructures to be inserted and removed from the subject as
needed, so that microstructures can be removed when measurements
are not being performed. This can be used to comfort, to reduce the
chance of infection, reduce biofouling, or the like.
[0320] As the microstructures are provided in a low-density
configuration, the force required is typically minimal, in which
case this could be achieved utilising an actuator that provides a
small force, such as piezoelectric actuator, or a mechanical
actuator, such as an offset motor, vibratory motor, or the like.
Other actuators could however be used, including any one or more of
an electric actuator, a magnetic actuator, a polymeric actuator, a
fabric or woven actuator, a pneumatic actuator, a thermal actuator,
a hydraulic actuator, a chemical actuator, or the like. For
example, a chemical or biochemical reaction, including exposure to
air, light, water or other substance, could trigger exothermic
release of energy, which can be used for to provide a mechanical
impulse to urge the substrate and hence microstructures into the
subject. It will also be appreciated that actuation could also be
achieved manually, by applying a force to the patch, or by using a
strap or similar to urge the patch against the subject.
[0321] In one specific example, this is achieved using a biasing
force, for example provided by a spring or electromagnetic
actuator, together with a vibratory, periodic or repeated force,
which can assist with penetration, for example by agitating the
microstructures to overcome the elasticity of the stratum corneum
and/or reduce friction for penetrating the epidermis and/or dermis,
as well as to reduce the force required to pierce a barrier. This
reduces the overall force required to penetrate the stratum
corneum. However, this is not essential and single continuous or
instantaneous forces could be used.
[0322] In one particular example, this is achieved using a
vibratory, periodic or repeated force, which can assist with
penetration, for example by agitating the microstructures to
overcome the elasticity of the stratum corneum. However, this is
not essential and single continuous or instantaneous forces could
be used.
[0323] The frequency of vibration used will vary depending upon the
preferred implementation and potentially the type of skin to which
the microstructures are applied, and could include any one or more
of at least 0.01 Hz, 0.1 Hz, 1 Hz, at least 10 Hz, at least 50 Hz,
at least 100 Hz, at least 1 kHz, at least 1 kHz, or at least 100
kHz and potentially up to several MHz. In one example, a varying
frequency could be used. The frequency could vary depending on a
wide range of factors, such as a time of application, and in
particular the length of time for which the application process has
been performed, the depth or degree of penetration, a degree of
resistance to insertion, or the like. In one example, the system
uses response signals measured via the microstructures in order to
detect when the barrier has been breached, such as when the
microstructures have penetrated the stratum corneum. Thus, the
frequency could be continuously varied, either increasing or
decreasing, until successful penetration is achieved, or depending
on a depth of penetration, which can be detected using response
signals, at which point the actuator can be deactivated. In another
example, the frequency starts high and progressively reduces as the
microstructures penetrate the barrier, and in particular the
stratum corneum.
[0324] In another example, the magnitude of the applied force can
also be controlled. The force used will vary depending on a range
of factors, such as the structure of the patch, the manner in which
the patch is applied, the location of application, the depth of
penetration, or the like. For example, patches with large numbers
of microstructures typically require an overall higher force in
order to ensure penetration, although for minimal numbers of
microstructures, such as 10 or so, a larger force may be required
to account for damping or loss from the substrate/skin. Similarly,
the force required to penetrate the stratum corneum, would
typically be higher than that required to penetrate the buccal
mucosa. In one example, the applied force could be any one or more
of at least 0.1 .mu.N, at least 1 .mu.N, at least 5 .mu.N, at least
10 .mu.N, at least 20 .mu.N, at least 50 .mu.N, at least 100 .mu.N,
at least 500 .mu.N, at least 1000 .mu.N, at least 10 mN, or at
least 100 mN, per microstructure and/or collectively. For example,
if there are 1000 microstructures, the force could be 100 mN in
total, or 100 mN per projection, leading to an overall 100 N
force.
[0325] Again, the force could vary, either increasing or
decreasing, depending on a time of application, a depth or degree
of penetration, which could be determined based on response
signals, for examining a change in measured impedance, or an
insertion resistance, or the like. In one specific example, the
force is progressively increased until a point of penetration, at
which point the force decreases.
[0326] As mentioned above, the force could be applied as a single
continuous or instantaneous force. However, more typically the
force is periodic. In this instance the nature of the periodic
motion could vary, this could for example, have any waveform,
including square waves, sine waves, triangular waves, variable
waveforms, or the like. In this case, the force could be an
absolute magnitude, or could be a peak-to-peak or Root Mean Square
(RMS) force.
[0327] Similarly, a magnitude of movement of the microstructures
can also be controlled. The degree of magnitude will depend on
factors, such as the length of the microstructures and the degree
of penetration required. The magnitude could include any one or
more of greater than 0.001 times a length of the microstructure,
greater than 0.01 times a length of the microstructure, greater
than 0.1 times a length of the microstructure, greater than a
length of the microstructure, greater than 10 times a length of the
microstructure, greater than 100 times a length of the
microstructure or greater than 1000 times a length of the
microstructure. The magnitude may also vary, either increasing or
decreasing, depending a time of application, a depth of
penetration, a degree of penetration or an insertion resistance.
Again, the magnitude may increase until a point of penetration and
then decrease after a point of penetration.
[0328] In the above example, the system can be configured to detect
aspects of the insertion process. In one example, this can be
achieved by monitoring the actuator, for example, monitoring the
current required by the actuator to achieve a specific movement,
which can in turn be used to detect, a depth of penetration, a
degree of penetration an insertion resistance, or the like, with
this then being used to control the actuator.
[0329] The actuator can also be used to apply mechanical
stimulation, which could be used for a variety of purposes. For
example, the actuator can be configured to physically disrupt or
dislodge a coating on the microstructures, physically stimulate the
subject, cause the microstructures to penetrate the barrier,
retract the microstructures from the barrier or retract the
microstructures from the subject.
[0330] The actuator is typically operatively coupled to the
substrate, which could be achieved using any suitable mechanism,
such as mechanical, electromechanical, or the like.
[0331] In one specific example, the actuator includes a spring or
electromagnetic actuator to provide a constant bias, and at least
one of a piezoelectric actuator and vibratory motor to apply a
vibratory force. The vibratory force is applied at a frequency that
is at least 10 Hz, less than 1 kHz and about 100-200 Hz. The
continuous force is typically greater than 1 N, less than 10 N and
about 5 N, whilst the vibratory force is at least 1 mN, less than
1000 mN and about 200 mN. The actuator is typically configured to
cause movement of the microstructures that is at least 10 .mu.m,
less than 300 .mu.m and about 50 .mu.m to 100 .mu.m.
[0332] In one example, the system includes a housing containing at
least the sensor and one or more electronic processing devices, and
optionally including other components, such as a signal generator,
actuator, power supply, wireless transceiver, or the like. In one
particular example, the housing provides reader functionality that
can be used to interrogate the microstructures, and which can be
provided in an integrated device, or could be provided remote to
the substrate and engaged or provided in proximity with the
substrate when readings are to be performed.
[0333] In the integrated configuration, the reader is typically
mechanically connected/integrated with the patch during normal use,
allowing measurements to be performed automatically. For example,
continual monitoring could be performed, with a reading being
performed every 1 second to daily or weekly, typically every 2 to
60 minutes, and more typically every 5 to 10 minutes. The timing of
readings can vary depending on the nature of the measurement being
performed and the particular circumstance. So for example, an
athlete might wish to undergo more frequent monitoring while
competing in an event, and then less frequent monitoring during
post event recovery. Similarly, for a person undergoing medical
monitoring, the frequency of monitoring may vary depending on the
nature and/or severity of a condition. In one example, the
frequency of monitoring can be selected based on user inputs and/or
could be based on a defined user profile, or the like.
[0334] In the integrated arrangement, the reader can be connected
to the patch using conventional resistance bridge circuitry, with
analogue to digital conversion being used to perform
measurements.
[0335] Alternatively, the reader can be separate, which allows the
reader to be removed when not in use, allowing the user to wear a
patch without any integrated electronics, making this less
intrusive. This is particularly useful for applications, such as
sports, geriatric and paediatric medicine, or the like, where the
presence of a bulkier device could impact on activities. In this
situation, the reader is typically brought into contact or
proximity with the patch allowing readings to be performed on
demand. It will be appreciated that this requires a user/person to
drive the interrogation. However, the reader could include alert
functionality to encourage interrogation.
[0336] Readings could be performed wirelessly, optionally using
inductive coupling to both power the patch and perform the reading
as will be described in more detail below, although alternatively,
direct physical contact could alternatively be used. In this
example, the microstructures and tissue form part of a resonant
circuit with discrete inductance or capacitance, allowing the
frequency to be used to determine the impedance and hence fluid
levels, or analyte levels or concentrations. Additionally, and/or
alternatively, ohmic contacts could be used, where the reader makes
electrical contact with connectors on the patch.
[0337] In either case, some analysis and interpretation of the
hydration signal or analyte level or concentration may be performed
in the reader, optionally allowing an indicator to be displayed on
the reader using an output, such as an LED indicator, LCD screen,
or the like. Additionally, and/or alternatively, audible alarms may
be provided, for example providing an indication in the event that
the subject is under or over hydrated or has an analyte level or
concentration outside an acceptable range. The reader can also
incorporate wireless connectivity, such as Bluetooth, Wi-Fi or
similar, allowing reading events to be triggered remotely and/or to
allow data, such as impedance values, hydration or analyte level or
concentration indicators, or the like to be transmitted to remote
devices, such as a client device, computer system, or cloud based
computing arrangement.
[0338] In use, the housing typically couples to the substrate,
allowing the housing and substrate to be attached and detached as
needed. In one example, this could be achieved utilising any
appropriate mechanism, such as electromagnetic coupling, mechanical
coupling, adhesive coupling, magnetic coupling, or the like. This
allows the housing and in particular sensing equipment to only be
connected to the substrate as needed. Thus, a substrate could be
applied to and secured to a subject, with a sensing system only
being attached to the substrate as measurements are to be
performed. However, it will be appreciated that this is not
essential, and alternatively the housing and substrate could be
collectively secured to the subject for example using an adhesive
patch, adhesive coating on the patch/substrate, strap, anchor
microstructures, or the like. In a further example, the substrate
could form part of the housing, so that the substrate and
microstructures are integrated into the housing.
[0339] When the housing is configured to attach to the substrate,
the housing typically includes connectors that operatively connect
to substrate connectors on the substrate, to thereby communicate
signals between the signal generator and/or sensor, and the
microstructures. The nature of the connectors and connections will
vary depending upon the preferred implementation and the nature of
the signal, and could include conductive contact surfaces, that
engage corresponding surfaces on the substrate, or could include
wireless connections, such as tuned inductive coils, wireless
communication antennas, or the like.
[0340] In one example, the system is configured to perform repeated
measurements over a time period, such as a few hours, days, weeks,
or similar. To achieve this, the microstructures can be configured
to remain in the subject during the time period, or alternatively
could be removed when measurements are not being performed. In one
example, the actuator can be configured to trigger insertion of the
microstructures into the skin and also allow for removal of the
microstructures once the measurements have been performed. The
microstructures can then be inserted and retracted as needed, to
enable measurements to be performed over a prolonged period of
time, without ongoing penetration of the skin. However, this is not
essential and alternatively short-term measurements can be
performed, in which case the time period can be less than 0.01
seconds, less than 0.1 seconds, less than 1 second or less than 10
seconds. It will be appreciated that other intermediate time frames
could also be used.
[0341] In one example, once measurements have been performed, the
one or more electronic processing devices analyse the measured
response signals to determine an indicator indicative of a health
and/or physiological status of the subject.
[0342] In one example, this is achieved by deriving at least one
metric, which can then be used to determine an indicator. For
example, the system could be configured to perform impedance
measurements, with the metric corresponding to an impedance
parameter, such as an impedance at a particular frequency, a phase
angle, or similar. The metric can then be used to derive
indicators, such as an indication of fluid levels, such as extra or
intra cellular fluid levels.
[0343] The manner in which this is performed will vary depending
upon the preferred implementation. For example, the electronic
processing devices could apply the metric to at least one
computational model to determine the indicator, with the
computational model embodying the relationship between a health
status and the one or more metrics. In this instance, the
computational model could be obtained by applying machine learning
to reference metrics derived from subject data measured for one or
more reference subjects having known health statuses. In this
instance, the health status could be indicative of organ function,
tissue function or cell function, could include the presence,
absence, degree or severity of a medical condition, or could
include one or more measures otherwise associated with a health
status, such as measurements of the presence, absence, level or
concentration of one or more analytes or measurements of other
biomarkers.
[0344] The nature of the model and the training performed can be of
any appropriate form and could include any one or more of decision
tree learning, random forest, logistic regression, association rule
learning, artificial neural networks, deep learning, inductive
logic programming, support vector machines, clustering, Bayesian
networks, reinforcement learning, representation learning,
similarity and metric learning, genetic algorithms, rule-based
machine learning, learning classifier systems, or the like. As such
schemes are known, these will not be described in any further
detail. In one example, this can include training a single model to
determine the indicator using metrics from reference subjects with
a combination of different health states, or the like, although
this is not essential and other approaches could be used.
[0345] Measured signals can also be used in other manners. For
example, changes in metrics over time can be used to track changes
in a health state or medical condition for a subject. Measured
signals can also be analysed in order to generate images or to
perform mapping. For example, tomography could be used to establish
a 2D or 3D image of a region of the subject based on impedance
measurements or similar. The signals could also be used in contrast
imaging, or the like.
[0346] In one example, the system can include a transmitter that
transmits measured subject data, metrics or measurement data such
as response signals or values derived from measured response
signals, allowing these to be analysed remotely.
[0347] In one particular example, the system includes a wearable
patch including the substrate and microstructures, and a monitoring
device (also referred to as a "reader") that performs the
measurements. The monitoring device could be attached or integrally
formed with the patch, for example mounting any required
electronics on a rear side of the substrate. Alternatively, the
reader could be brought into contact with the patch when a reading
is to be performed. In either case, connections between the
monitoring device could be conductive contacts, but alternatively
could be indicative coupling, allowing the patch to be wirelessly
interrogated and/or powered by the reader.
[0348] The monitoring device can be configured to cause a
measurement to be performed and/or to at least partially process
and/or analyse measurements. The monitoring device can control
stimulation applied to at least one microstructure, for example by
controlling the signal generator and/or switches as needed. This
allows the monitoring device to selectively interrogate different
microstructures, allowing different measurements to be performed,
and/or allowing measurements to be performed at different
locations. This also allows microstructures to be selectively
stimulated, for example, allowing different therapies to be applied
to the subject. Thus by selectively stimulating microstructures, to
thereby selectively release therapeutic materials, this could be
used in order to provide dosage control, or to deliver different
therapeutic materials.
[0349] The monitoring device could also be used to generate an
output, such as an output indicative of the indicator or a
recommendation based on the indicator and/or cause an action to be
performed. Thus, the monitoring device could be configured to
generate an output including a notification or an alert. This can
be used to trigger an intervention, for example, indicating to a
user that action is required. This could simply be an indication of
an issue, such as telling a user they are dehydrated or have
elevated troponin levels and/or could include a recommendation,
such as telling the user to rehydrate, or seek medical attention or
similar. The output could additionally and/or alternatively,
include an indication of an indicator, such as a measured value, or
information derived from an indicator. Thus, a hydration level or
analyte level or concentration could be presented to the user.
[0350] The monitoring device could also be configured to trigger
other actions,
[0351] The output could be used to alert a caregiver that an
intervention is required, for example transferring a notification
to a client device and/or computer of the caregiver. In another
example, this could also be used to control remote equipment. For
example, this could be used to trigger a drug delivery system, such
as an electronically controlled syringe injection pump, allowing an
intervention to be triggered automatically. In a further example, a
semi-automated system could be used, for example providing a
clinician with a notification including an indicator, and a
recommended intervention, allowing the clinician to approve the
intervention, which is then performed automatically.
[0352] In one example, the monitoring device is configured to
interface with a separate processing system, such as a client
device and/or computer system. In this example, this allows
processing and analysis tasks to be distributed between the
monitoring device and the client device and/or computer system. For
example, the monitoring device could perform partial processing of
measured response signals, such as filtering and/or digitising
these, providing an indication of the processed signals to a remote
process system for analysis. In one example, this is achieved by
generating subject data including the processed response signals,
and transferring this to a client device and/or computer system for
analysis. Thus, this allows the monitoring device to communicate
with a computer system that generates, analyses or stores subject
data derived from the measurement data. This can then be used to
generate an indicator at least partially indicative of a health
status associated with the subject.
[0353] It will also be appreciated that this allows additional
functionality to be implemented, including transferring
notifications to clinicians, or other caregivers, and also allowing
for remote storage of data and/or indicators. In one example, this
allows recorded measurements and other information, such as derived
indicators, details of applied stimulation or therapy and/or
details of other resulting actions, to be directly incorporated
into an electronic record, such as an electronic medical
record.
[0354] In one example, this allows the system to provide the data
that will underpin the growing telehealth sector empowering
telehealth systems with high fidelity and accurate clinical data to
enable remote clinicians to gain the information they require, and
they will be highly valued both in central hospitals and in rural
areas away from centralized laboratories and regional hospitals.
With time to treatment a strong predictor of improved clinical
outcomes with heart attack patients, decentralized populations
cannot rely solely on access to conventional large-scale hospitals.
Accordingly, the system can provide a low cost, robust and accurate
monitoring system, capable for example of diagnosing a heart
attack, and yet being provided at any local health facility and as
simple as applying a patch device. In this example, resources could
be dispatched quickly for patients who test positive to troponin I,
with no delay for cardiac troponin laboratory blood-tests.
Similarly patients determined to be low-risk could be released
earlier and with fewer invasive tests, or funnelled into other
streams via their GP etc.
[0355] In a further example, a client device such as a smart phone,
tablet, or the like, is used to receive measurement data from the
wearable monitoring device, generate subject data and then transfer
this to the processing system, with the processing system returning
an indicator, which can then be displayed on the client device
and/or monitoring device, depending on the preferred
implementation.
[0356] However, this is not essential and it will be appreciated
that some or all of the steps of analysing measurements, generating
an indicator and/or displaying a representation of the indicator
could be performed on board the monitoring device.
[0357] Again, it will be appreciated that similar outputs could
also be provided to or by a remote processing system or client
device, for example, alerting a clinician or trainer that a subject
or athlete requires attention, that an intervention should be
performed, controlling equipment, such as drug delivery devices, or
the like.
[0358] The reader could be configured to perform measurements
automatically when integrated into or permanently/semi permanently
attached to the patch, or could perform measurements when brought
into contact with the patch if the reader is separate. In this
latter example, the reader can be inductively coupled to the
patch.
[0359] Thus, it will be appreciated that functionality, such as
processing measured response signals, analysing results, generating
outputs, controlling measurement procedures and/or therapy delivery
could be performed by an on-board monitoring device, and/or could
be performed by remote computer systems, and that the particular
distribution of tasks and resulting functionality can vary
depending on the preferred implementation.
[0360] In one example, the system includes a substrate coil
positioned on the substrate and operatively coupled to one or more
microstructure electrodes, which could include microstructures that
are electrodes, or microstructures including electrodes thereon. An
excitation and receiving coil is provided, typically in a housing
of a measuring device, with the excitation and receiving coil being
positioned in proximity to the substrate coil in use. This is
performed to inductively couple the excitation and receiving coil
to the substrate coils, so that when an excitation signal is
applied to the drive coil, this induces a signal in the substrate
coil, which, in association with the electrodes and other reactive
components on the substrate, may form a resonant circuit. As a
result, the signal frequency, amplitude and damping (Q) of the
resonant circuit on the substrate will be reflected in signal
observed in the excitation and receive coil, which in turn alters
the drive signal applied to the excitation and receiving coil, for
example by changing the frequency, phase or magnitude of the
signal, allowing this to act as a response signal, for example
allowing a bioimpedance or biocapacitance to be measured.
[0361] This can be used in a variety of manners, but in one
example, the one or more microstructure electrodes are configured
to bind one or more analytes of interest, such that the response
signal is dependent on a presence, absence, level or concentration
of analytes of interest. This can be achieved in a variety of ways
as discussed supra, such as coating the microstructures with a
binding agent or forming the microstructures from material
comprising a binding agent, so that analytes interact with the
microstructure electrodes, hence changing their electrical
properties and thereby changing the characteristics of the response
signal. For example, this could include having the analytes bind to
a coating or the material forming the microstructure, such as a
molecularly imprinted polymer.
[0362] Detection of analytes could be performed in any manner, and
this could involve examining changes in the response signal over
time, for example as a level or concentration of analytes in the
vicinity of the microstructure electrodes changes. Alternatively,
in another example, two sets of microstructure electrodes are used,
which are driven independently, with one acting as a control, and
others being selectively responsive to one or more analytes so
differences in measured signals are indicative of changes in
analyte level or concentration.
[0363] In this example, the system typically includes a first
substrate coil positioned on a substrate and operatively coupled to
one or more first microstructure electrodes, a second substrate
coil positioned on a substrate and operatively coupled to one or
more second microstructure electrodes, the second microstructure
electrodes being configured to interact with analytes of interest.
At least one drive coil is positioned in proximity to at least one
of the first and second substrate coils such that alteration, such
as attenuation, or a phase or frequency change, of a drive signal
applied acts as a response signal. In this case, the one or more
electronic processing devices use the first and second response
signals, and in particular difference between the first and second
response signals to determine a presence, absence, level or
concentration of analytes of interest.
[0364] In the case of multiple substrate coil and electrode
combinations forming resonant circuits, each may be intentionally
designed by selection of fixed reactive components either inductive
or capacitive to possess a different resonant frequency, thereby
permitting a means of frequency based multiplexing of an entire
array with a single excitation and receive coil.
[0365] A further example of a system for performing measurements in
the biological subject will now be described with reference to
FIGS. 3A to 3K.
[0366] In this example, the system includes a monitoring device
320, including a sensor 321 and one or more electronic processing
devices 322. The system further includes a signal generator 323, a
memory 324, an external interface 325, such as a wireless
transceiver, an actuator 326, and an input/output device 327, such
as a touchscreen or display and input buttons, connected to the
electronic processing device 322. The components are typically
provided in a housing 330, which will be described below.
[0367] The nature of the signal generator 323 and sensor 321 will
depend on the measurements being performed, and could include a
current source and voltage sensor, laser or other electromagnetic
radiation source, such as an LED, and a photodiode or CCD sensor,
or the like. The actuator 326 is typically a spring or
electromagnetic actuator in combination with a piezoelectric
actuator or vibratory motor coupled to the housing, to bias and
vibrate the substrate relative to an underside of the housing, to
thereby urge the microstructures into the skin, whilst the
transceiver is typically a short-range wireless transceiver, such
as a Bluetooth system on a chip (SoC).
[0368] The processing device 322 executes software instructions
stored in the memory 324 to allow various processes to be
performed, including controlling the signal generator 323,
receiving and interpreting signals from the sensor 321, generating
measurement data and transmitting this to a client device or other
processing system via the transceiver 325. Accordingly, the
electronic processing device is typically a microprocessor,
microcontroller, microchip processor, logic gate configuration,
firmware optionally associated with implementing logic such as an
FPGA (Field Programmable Gate Array), or any other electronic
device, system or arrangement.
[0369] In use the monitoring device 320 is coupled to a patch 310,
including a substrate 311 and microstructures 312, which are
coupled to the sensor 321 and/or signal generator 323 via
connections 313. The connections could include physical conductive
connections, such as conductive tracks, although this is not
essential and alternatively wireless connections could be provided,
such inductive coupling or radio frequency wireless connections. In
this example, the patch further includes anchor microstructures 314
that are configured to penetrate into the dermis and thereby assist
in securing the patch to the subject.
[0370] An example of the patch 310 is shown in more detail in FIGS.
3B and 3C. In particular, in this example the substrate 311 is
generally rectangular, with round corners to avoid discomfort when
the substrate is applied to the subject's skin. The substrate 311
includes anchor microstructures 314 are provided proximate corners
of the substrate 311 to help secure the substrate, whilst
measurement microstructures 312 are arranged in an array on the
substrate. In this example, the array has a regular grid formation,
with the microstructures 312 being in provided in equally spaced
rows and columns, but this is not essential and alternative spacing
configurations could be used, as will be described in more detail
below.
[0371] In one example, the substrate is also formed from multiple
substrate layers 311.1, 311.2, which can assist in creating
internal structures, such as connections to the microstructures,
coils, or the like, as will be described in more detail below. In a
manner similar to that described below with respect to a backing,
the substrate could also include different regions or layers having
different material properties, or the like.
[0372] In the example of FIGS. 3B and 3C, four connectors 315 are
provided which are connected to respective microstructures 312 via
connections 313 to allow stimulation signals and response signals
to be applied to and measured from two sets of respective
microstructures. This can be used to allow for symmetric or
differential application and detection of signals, as opposed to
asymmetric or single-ended application or detection, which is
typically performed relative to a ground reference, and which is in
turn generally noisier. However, it will be appreciated that for
some detection modalities, such as optical detection, or the like,
this is not relevant and single connections 315 may be
provided.
[0373] The substrate also includes coupling members 316, such as
magnets, which can be used to attach the substrate to the housing
330.
[0374] In the example of FIGS. 3D and 3E, the housing 330 is a
generally rectangular housing. The measuring device can optionally
have a form factor similar to a watch, or other wearable device, in
which case a strap 331 is included that allows the housing to be
secured to the user. However, this is not essential and other
securing mechanisms could be used. Alternatively, the housing could
simply be brought into engagement with the patch and held in
position each time a measurement is performed. In this example, the
housing includes coupling members 332, such as magnets, or the
like, which can engage with corresponding coupling members 316 on
the substrate allowing the substrate to be secured to the housing.
Whilst any form of coupling member could be used, the use of
magnets is particularly advantageous as these can be contained
within the housing 330, allowing the housing to be sealed, and can
also act to ensure correct alignment of the substrate 310, for
example by having polarities of the magnets guide a relative
orientation of the substrate 310 and housing 330.
[0375] However, it will be appreciated that this configuration is
for the purpose of illustration only, and other arrangements could
be used. For example, the substrate could form part of an adhesive
patch, which is applied to the subject and retained in place.
Alternatively, adhesive could be provided on a surface of the
substrate to adhere the substrate directly to the subject. The
housing 330, could then be selectively attached to the patch, for
example, using magnetic coupling, thereby allowing measurements to
be performed as needed.
[0376] In this example, the substrate could be a flexible
substrate, which can be achieved using a woven or non-woven fabric
or other suitable material, with microstructures directly attached
thereto. More typically however, flexibility is achieved using a
number of individual substrates 311 mounted on a flexible backing
319, to form a segmented substrate, as shown in FIG. 3F. It will be
appreciated that such arrangements can be used in a wide variety of
circumstances, including having the substrates mounted to a strap
or the like, for attachment to the subject.
[0377] A number of further variations are shown in FIGS. 3G to
31.
[0378] Specifically in the example of FIG. 3G, the backing 319 is
formed from multiple backing layers 319.1, 319.2, with two being
shown in the example for the purpose of illustration only. The use
of multiple layers can be beneficial in achieving desired
properties, for example to provide adhesive, or waterproof layers,
or the like.
[0379] In the example of FIG. 3H, the backing layer has multiple
interspersed regions 319.3, which can be used for particular
purposes, such as to allow for easier attachment of the substrates
311, to provide connectivity to a measuring device 320, to allow
for increased flexibility between the substrates 311, or the like.
In this example, interspersed regions are substantially aligned
with the substrates, although it will be appreciated that this is
not essential, and they could be provided at other locations.
[0380] A further example is shown in FIG. 3I, which includes a
number of shape modifications, including thinner regions 319.4,
located between substrates, which could be used to enhance
flexibility, or thicker regions 319.5 between the substrates, which
could increase strength. Similarly thinner or thicker regions
319.5, 319.6 could be provided in line with the substrates, for
example to enhance strength, flexibility, connection to a measuring
device, or the like.
[0381] Whilst these features have been described with reference to
a backing layer, it will be appreciated that similar approaches
could be used for the substrate itself.
[0382] An example of an actuator configuration to assist with
applying a patch will now be described with reference to FIG.
3J.
[0383] In this example, the housing 330 includes a mounting 333 to
which the actuator 326, such as a piezoelectric actuator, or
vibrating motor, is attached. The actuator 326 is aligned with an
opening 334 in an underside of the housing 330, with an arm 326.1
coupled to the actuator 326 extending through the opening 334,
which may be sealed using an O-ring 334.1, or other similar
arrangement.
[0384] The patch substrate 311 is positioned adjacent the underside
of the housing 330, with magnets 316, 332 being arranged to urge
the substrate 311 towards the housing 330. The arm 326.1 engages
the substrate to thereby transmit forces from the actuator 326 to
the substrate 311, allowing the substrate and hence microstructures
312, 314, to be vibrated to aid insertion of the microstructures
into the subject. Specifically, this arrangement transmits forces
directly to the substrate 311, allowing forces in the substrate to
be maximised, whilst minimising vibration of the housing 330.
[0385] A further example actuator arrangement will now be described
with reference to FIG. 3K.
[0386] In this example, the actuator arrangement includes an
actuator housing 335 having a base 335.1 including an opening
335.2. The housing contains a spring 336 and mounting 337, which in
use supports a patch 310 (and optional integrated reader). The
mounting also optionally contains a piezoelectric actuator or
offset motor 338.
[0387] In use, the actuator housing 335 is positioned so that a
base 335.1 of the housing 335 abuts against the subject's skin,
with the patch at least partially projecting through the opening
335.2. In one example, this is achieved by having an operator hold
the actuator housing. However, this is not essential and
additionally and/or alternatively, the actuator housing could be
integrated into and/or form part of a monitoring device as
described above.
[0388] In use, the spring 336 is configured to apply a continuous
biasing force to the mounting 337, so the patch 310 is urged
against the subject's skin. Additionally, the piezoelectric
actuator or offset motor 338 can cause the mounting 337, and hence
patch 310, to vibrate, thereby facilitating piercing and/or
penetration of the stratum corneum by the microstructures.
[0389] Example microstructure arrangements will now be described in
more detail with reference to FIGS. 4 to 8.
[0390] In the example of FIG. 4A, different length microstructures
are shown with a first microstructure 412.1 penetrating the stratum
corneum and viable epidermis, but not breaching the dermis, a
second microstructure 412.2 entering the dermis but only just
passes the dermal boundary, whereas a third microstructure 412.3
penetrates the dermal layer at greater distance. It will be
appreciated that the length of structure used will vary depending
upon the intended application of the device, and specifically the
nature of the barrier to be breached.
[0391] In the example of FIG. 4B, pairs of microstructures are
provided with a first microstructure pair 412.4 having a closer
spacing and a second microstructure pair 412.5 having a relatively
large spacing, which can be used to enable different properties to
be detected, or different forms of stimulation to be performed.
[0392] For example, a greater electrode spacing can be used to
perform impedance measurements of interstitial fluid and other
tissues and liquids between the electrodes, whereas closer spaced
electrodes are more suited to performing capacitive sensing to
detect different analytes present on a surface of the
electrodes.
[0393] Additionally, the electrical field strength generated by
applying a signal to the first and second microstructure pairs are
shown in FIGS. 4C and 4D, highlighting that the field strength
between the electrodes decreases as the spacing increases, which in
turn impacts on the ability to perform stimulation. For example, by
providing an array of closely spaced microstructures, this can be
used to generate a highly uniform field within the subject, without
requiring a large applied field. This can be used to allow the
field to be used for stimulation, for example, to perform
electroporation, or the like.
[0394] The microstructures can have a range of different shapes,
and examples are shown in FIGS. 4E to 4J. Specifically, these
illustrate circular, rectangular, octagonal, cruciform, and star
shapes. The shapes used will vary depending on the intended
application. For example, larger numbers of the microstructures can
be useful to provide multiple different electrode surfaces, whilst
a greater overall surface area can be useful to maximise the amount
of coating. Similarly, acute angled surfaces can, such as the
cruciform and star arrangements, can allow coating to be used to
provide an overall circular profile, with different coating depths
around the microstructure.
[0395] A specific example of a plate microstructure is shown is
shown in FIGS. 5A to 5C.
[0396] In this example, the microstructure is a plate having a body
512.1 and a tip 512.2, which is tapered to facilitate penetration
of the microstructure 512 into the stratum corneum. In this
example, electrode plates 517 are provided on each side of the
microstructure, with these being coupled via a single connection
513 to a connector 515 for onward connection to a sensor 321 and/or
signal generator 323. This allows a signal to be measured from or
applied to the electrode plates collectively. It will be
appreciated however that this is not essential and independent
connections could be provided allowing each of the electrodes to be
driven or sensed independently. Additionally, each electrode 517
could be subdivided into multiple independent segments 517.1,
517.2, 517.3, 517.4, such that each face includes multiple
electrodes.
[0397] As shown in FIGS. 5C and 5D, different arrangements could be
used but in general, pairs of microstructures are formed with the
microstructures facing each other allowing signals to be applied
between the microstructures or measured between the
microstructures. Again, different separations between electrodes in
pairs of electrodes can be used to allow different measurements to
be performed and/or to alter the profile of stimulation of the
tissue between the electrodes.
[0398] A further example of a blade microstructure is shown is
shown in FIGS. 5E and 5F.
[0399] In this example, the microstructure is an elongate body
512.1 and tip 512.2, which is tapered to facilitate penetration of
the microstructure 512. This is generally similar in profile to the
plate arrangement described above, but in this example is
significantly wider, and in one particular example, can extend
substantially the entire distance across the substrate. In this
example, the microstructures include multiple electrode plates 517
on each side of the microstructure. In this case, the substrate can
include multiple spaced parallel blades, allowing signals to be
applied across or measured between the electrodes on different
blades. However, it will be appreciated that other configurations
could be used, such as providing a single electrode, segmented
electrodes, or having the entire microstructure act as an
electrode.
[0400] In the example, shown the blade tip is parallel to the
substrate, but this is not essential and other configurations could
be used, such as having a sloped tip, so that the blade penetrates
progressively along the length of the blade as it is inserted,
which can in turn facilitate penetration. The tip may also include
serrations, or similar, to further enhance penetration.
[0401] As mentioned above, in one example, microstructures are
provided in a regular grid arrangement. However, in another
example, the microstructures are provided in a hexagonal grid
arrangement as shown in FIG. 5G. This is particularly advantageous
as each microstructure is equally spaced to all of the nearest
neighbour microstructures, as shown by the arrows, meaning
measurements can be performed relative to any adjacent
microstructure without requiring response or stimulation signals to
be modified to account for different spacings.
[0402] A further example arrangement is shown in FIGS. 5H and 51,
in which microstructures 512 are arranged in pairs 512.3, and with
pairs arranged in offset rows, 512.4, 512.5. In this example, pairs
in different rows are arranged orthogonally, so that the
microstructures extend in different directions. This avoids all
microstructures being aligned, which can in turn render a patch
vulnerable to lateral slippage in a direction aligned with the
microstructures. Additionally arranging the pairs orthogonally
reduces interference, such as cross talk, between different pairs
of electrodes, improving measurement accuracy and accounting for
tissue anisotropy, particularly when measurements are being
performed via multiple microstructure pairs simultaneously.
[0403] A further example arrangement is shown in FIGS. 5H to 5K, in
which microstructures 512 are arranged in pairs 512.3, and with
pairs arranged in offset rows, 512.4, 512.5. In this example, pairs
in different rows are arranged orthogonally, so that the
microstructures extend in different directions. This avoids all
microstructures being aligned, which can in turn render a patch
vulnerable to lateral slippage in a direction aligned with the
microstructures. Additionally arranging the pairs orthogonally
reduces interference, such as cross talk, between different pairs
of electrodes, improving measurement accuracy and accounting for
tissue anisotropy, particularly when measurements are being
performed via multiple microstructure pairs simultaneously.
[0404] In one example, pairs of microstructures in each row can be
provided with respective connections 513.41, 513.42; 513.51,
513.52, allowing an entire row of microstructure pairs to be
interrogated and/or stimulated simultaneously, whilst allowing
different rows to be interrogated and/or stimulated
independently.
[0405] A Scanning Electron Microscopy (SEM) image showing an array
of pairs of offset plate microstructures is shown in FIG. 5K.
[0406] Specific examples of microstructures for performing
measurements in the epidermis are shown in FIGS. 5L and 5M.
[0407] In this example, the microstructures are plates or blades,
having a body 512.1, with a flared base 512.11, where the body
joins the substrate, to enhance the strength of the microstructure.
The body narrows at a waist 512.12 to define shoulders 512.13 and
then extends to a tapered tip 512.2, in this example, via an
untapered shaft 512.14. Typical dimensions are shown in Table 2
below.
TABLE-US-00002 TABLE 2 Parameter Min. Typical Max. Units Length 50
150 300 microns Width 50 150 300 microns Thickness 10 25 50 microns
Density 100 600 5000 cm.sup.-2 Tip radius 0.1 1 5 microns Surface
area per 2,000 22,500 200,000 micron.sup.2 electrode Buttress width
at 30 75 150 microns base
[0408] An example of a pair of the microstructures of FIGS. 5L and
5M on insertion into a subject is shown in FIG. 5N.
[0409] In this example, the microstructures are configured so that
the tip 512.2 penetrates the stratum corneum SC and enters the
viable epidermis VE. The waist 512.12, and in particular the
shoulders 512.13 abut the stratum corneum SC so that the
microstructure does not penetrate further into the subject, and so
that the tip is prevented from entering the dermis. This helps
avoid contact with nerves, which can lead to pain.
[0410] In this configuration, the body 512.1 of the microstructure
can be coated with a layer of insulating material (not shown), with
only the tip exposed. As a result a current signal applied between
the microstructures, will generate an electric field E within the
subject, and in particular within the viable epidermis VE, so that
measurements reflect fluid levels in the viable epidermis VE.
[0411] However, it will be appreciated that other configurations
can be used. For example, in the arrangement of FIG. 5O, the shaft
512.14 is lengthened so the tip 512.2 enters the dermis, allowing
dermal (and optional epidermal) measurements to be performed.
[0412] In this example, typical dimensions are shown in Table 3
below.
TABLE-US-00003 TABLE 3 Parameter Min. Typical Max. Units Length 50
250 450 microns Width 50 250 450 microns Thickness 10 30 50 microns
Density 100 600 5000 cm.sup.-2 Tip radius 0.1 1 5 microns Surface
area per 10,000 62,500 427,000 micron.sup.2 electrode Buttress
width 30 75 150 microns at base
[0413] An example of the inter and intra pair spacing for these
configurations are shown in Table 4 below.
TABLE-US-00004 TABLE 4 Parameter Min. Typical Max. Units Separation
10 100 1000 microns between microstructures in a group or pair
Separation 200 500 1000 microns between groups of
microstructures
[0414] A further example arrangement is shown at FIGS. 6A and 6B,
with the microstructure again including a generally similar plate
like arrangement, with the microstructure including spaced apart
prongs 612.2, each having an electrode 617 thereon, so that the
electrodes are on faces between the prongs 612.2, again allowing
for the application of a highly uniform field, or to allow
capacitive sensing to be performed.
[0415] A further example of a microstructure is shown at FIG. 7A
and FIG. 7B, which includes a body 512.1 containing a core 513 that
is conductive, covered by an insulating layer 512.1, which in one
example could be a polymer or other material. In this instance, the
core 513 terminates at an opening 513.2 allowing electrical signals
to be communicated via the outlet. Additionally, and/or
alternatively, ports 513.3 may also be provided extending through
the insulating layer, allowing electrical signals to be
communicated midway along the structure as shown at FIG. 7B,
allowing measurements to be performed at targeted depths within the
viable epidermis and/or dermis.
[0416] It will also be appreciated that when pairs of
microstructures are used, electrodes could be provided on an inner
face of the pair only, for example, by insulating an outer face of
the pair, to thereby reduce electrical interference between
different pairs of microstructures.
[0417] An alternative technique for manufacturing microstructures
will now be described with reference to FIGS. 8A to 8E.
[0418] In this example, a carrier wafer 891 is provided and spin
coated with a photopolymer layer 892. The photopolymer layer 892 is
selectively exposed to UV illumination and crosslinked, to create
structural regions 892.1, which in this example form a substrate. A
second photopolymer layer 893 is spun coated onto the first layer
891, and exposed to UV illumination and cross linked to form second
structural regions 893.1, which in this example form
microstructures, extending from the substrate. The carrier wafer
and non-crosslinked polymer are removed to create the
microstructures shown in FIG. 8D.
[0419] It will be appreciated that this layering technique can be
used to create a wide range of different microstructure
configurations, and alternative design is shown in FIG. 8E.
[0420] In one example, the monitoring device operates as part of a
distributed architecture, an example of which will now be described
with reference to FIG. 9.
[0421] In this example, one or more processing systems 910 are
coupled via communications networks 940, and/or one or more local
area networks (LANs), to a number of client devices 930 and
monitoring devices 920. The monitoring devices 920 could connect
direction to the networks, or could be configured to connect to a
client device 930, which then provides onward connectivity to the
networks 940. It will be appreciated that the configuration of the
networks 940 are for the purpose of example only, and in practice
the processing systems 910, client devices 930 and monitoring
devices 930 can communicate via any appropriate mechanism, such as
via wired or wireless connections, including, but not limited to
mobile networks, private networks, such as an 802.11 networks, the
Internet, LANs, WANs, or the like, as well as via direct or
point-to-point connections, such as Bluetooth, or the like.
[0422] In one example, each processing system 910 is configured to
receive subject data from a monitoring device 920 or client device
930, and analyse the subject data to generate one or more health
status indicators, which can then be provided to a client device
930 or monitoring device 920 for display. Whilst the processing
system 910 is a shown as a single entity, it will be appreciated
that the processing system 910 can be distributed over a number of
geographically separate locations, for example by using processing
systems 910 and/or databases that are provided as part of a
cloud-based environment. However, the above described arrangement
is not essential and other suitable configurations could be
used.
[0423] An example of a suitable processing system 910 is shown in
FIG. 10.
[0424] In this example, the processing system 910 includes at least
one microprocessor 1000, a memory 1001, an optional input/output
device 1002, such as a keyboard and/or display, and an external
interface 1003, interconnected via a bus 1004 as shown. In this
example the external interface 1003 can be utilised for connecting
the processing system 910 to peripheral devices, such as the
communications network 940, databases 1011, other storage devices,
or the like. Although a single external interface 1003 is shown,
this is for the purpose of example only, and in practice multiple
interfaces using various methods (eg. ethernet, serial, USB,
wireless or the like) may be provided.
[0425] In use, the microprocessor 1000 executes instructions in the
form of applications software stored in the memory 1001 to allow
the required processes to be performed. The applications software
may include one or more software modules, and may be executed in a
suitable execution environment, such as an operating system
environment, or the like.
[0426] Accordingly, it will be appreciated that the processing
system 910 may be formed from any suitable processing system, such
as a suitably programmed client device, PC, web server, network
server, or the like. In one particular example, the processing
system 910 is a standard processing system such as an Intel
Architecture based processing system, which executes software
applications stored on non-volatile (e.g., hard disk) storage,
although this is not essential. However, it will also be understood
that the processing system could be any electronic processing
device such as a microprocessor, microchip processor, logic gate
configuration, firmware optionally associated with implementing
logic such as an FPGA (Field Programmable Gate Array), or any other
electronic device, system or arrangement.
[0427] An example of a suitable client device 930 is shown in FIG.
11.
[0428] In one example, the client device 930 includes at least one
microprocessor 1100, a memory 1101, an input/output device 1102,
such as a keyboard and/or display, and an external interface 1103,
interconnected via a bus 1104 as shown. In this example the
external interface 1103 can be utilised for connecting the client
device 930 to peripheral devices, such as the communications
networks 940, databases, other storage devices, or the like.
Although a single external interface 1103 is shown, this is for the
purpose of example only, and in practice multiple interfaces using
various methods (eg. Ethernet, serial, USB, wireless or the like)
may be provided.
[0429] In use, the microprocessor 1100 executes instructions in the
form of applications software stored in the memory 1101 to allow
communication with the processing system 910 and/or monitoring
device 920.
[0430] Accordingly, it will be appreciated that the client devices
1130 may be formed from any suitable processing system, such as a
suitably programmed PC, Internet terminal, lap-top, or hand-held
PC, and in one preferred example is either a tablet, or smart
phone, or the like. Thus, in one example, the client device 1130 is
a standard processing system such as an Intel Architecture based
processing system, which executes software applications stored on
non-volatile (e.g., hard disk) storage, although this is not
essential. However, it will also be understood that the client
devices 1130 can be any electronic processing device such as a
microprocessor, microchip processor, logic gate configuration,
firmware optionally associated with implementing logic such as an
FPGA (Field Programmable Gate Array), or any other electronic
device, system or arrangement.
[0431] Examples of the processes for performing measurements and
generating indicators will now be described in further detail. For
the purpose of these examples it is assumed that one or more
processing systems 910 acts to analyse received subject data and
generate resulting indicators. Measurements are performed by the
monitoring devices 920, with subject data being transferred to the
processing systems 910 via the client devices 230. In one example,
to provide this in a platform agnostic manner, allowing this to be
easily accessed using client devices 930 using different operating
systems, and having different processing capabilities, input data
and commands are received from the client devices 930 using via a
webpage, with resulting visualisations being rendered locally by a
browser application, or other similar application executed by the
client device 930. The processing system 910 is therefore typically
a server (and will hereinafter be referred to as a server) which
communicates with the client device 930 and/or monitoring device
920, via a communications network 940, or the like, depending on
the particular network infrastructure available.
[0432] To achieve this the server 910 typically executes
applications software for hosting webpages, as well as performing
other required tasks including storing, searching and processing of
data, with actions performed by the processing system 910 being
performed by the processor 1000 in accordance with instructions
stored as applications software in the memory 1001 and/or input
commands received from a user via the I/O device 1002, or commands
received from the client device 1030.
[0433] It will also be assumed that the user interacts with the
server 910 via a GUI (Graphical User Interface), or the like
presented on the client device 930, and in one particular example
via a browser application that displays webpages hosted by the
server 910, or an App that displays data supplied by the server
910. Actions performed by the client device 930 are performed by
the processor 1100 in accordance with instructions stored as
applications software in the memory 1101 and/or input commands
received from a user via the I/O device 1102.
[0434] However, it will be appreciated that the above described
configuration assumed for the purpose of the following examples is
not essential, and numerous other configurations may be used. It
will also be appreciated that the partitioning of functionality
between the monitoring devices 920, client devices 930, and the
server 910 may vary, depending on the particular
implementation.
[0435] An example of process for performing measurements on a
subject will now be described in more detail with reference to
FIGS. 12A and 12B.
[0436] In this example, a process for applying a patch including
the substrate and microstructures is shown in steps 1200 to 1230,
whilst a measurement process is shown in steps 1235 to 1260. In
this regard, it will be appreciated that for patches that are used
for performing multiple measurements over a period of time, steps
1200 to 1230 would only be performed a single time, with steps 1235
to 1260 being repeated as needed.
[0437] Furthermore, for the purpose of this example, it is assumed
that the system includes a reader formed by the housing 330 and
associated signal generator, sensor and processing electronics. The
reader could be integral with the patch 310 and/or separate from
the patch 310 depending on the preferred implementation.
[0438] At step 1200, the substrate is provided in a desired
position, with the substrate and microstructures in place against
the subject. At step 1205, assuming the reader is not integrated
into the patch 310, the housing 330 is attached to the substrate
311, for example, by magnetically or otherwise coupling the housing
and substrate, or by holding the housing in contact with the patch
310.
[0439] At step 1210, the processing device 322 selects a
frequency/magnitude for the actuator. This can be a standard value
and/or might depend on the barrier to be breached, so that
different values might be selected for different sites on a
subject, and/or for different subjects.
[0440] At step 1215, the actuator 326 is controlled, to thereby
begin vibration of the microstructures, and hence facilitate
movement of the microstructures within the subject.
[0441] At step 1220 stimulation is optionally applied, with
response signals being measured at step 1225, allowing the
processing device 322 to monitor breaching of the functional
barrier and/or a depth of penetration. The mechanism for achieving
this will depend on the nature of the response signals and optional
stimulation. For example, the stimulation and response could be
used to derive an impedance, with the impedance value altering as
the microstructures penetrate the stratum corneum and enter the
viable epidermis.
[0442] At step 1230, the processing device 322 optionally
determines if breaching or penetration are complete and if not, the
process returns to step 1210 to select a different frequency and/or
magnitude. Thus, this process allows the frequency and/or magnitude
of any applied force to be adjusted continuously as the substrate
and microstructures are applied, and in particular as the
microstructures breach and optionally penetrate the functional
barrier. In one example, this is used to allow the frequency to
decrease during insertion, whilst the force progressively increases
until the barrier is breached, at which point the force decreases.
In this regard, it has been found that this can facilitate
penetration of the barrier.
[0443] Once the patch is applied, measurements can commence. In
this regard, if the reader is integrated into the patch,
measurements can be performed as needed. Alternatively, if the
reader is separate, this may require the reader be brought into
proximity and/or contact with the patch, to allow a measurement to
be performed.
[0444] In this example, at step 1235 the monitoring device 920
applies one or more stimulatory signals to the subject, and then
measures response signal at step 1240. The response signals are
measured by the sensor 321, which generates measurement data that
is provided to the processing device 322 at step 1245. In this
example, the monitoring device 920 then transfer the measurement
data to a client device 930 for further processing. In particular,
the client device 930 might perform preliminary pre-processing of
data and may append additional information, for example derived
from onboard sensors, such as GPS or other like, to thereby add
time or location information, or the like. This information can be
useful in circumstances, such as tracking spread of infectious
diseases or similar.
[0445] The resulting data is collated, for example by creating
subject data, which can then be transferred to a server 910
allowing this to be analysed at step 1250. However, it will also be
appreciated that the analysis could be performed on board the
reader, and an indicator derived by performing the analysis could
be displayed on the reader.
[0446] The nature of the analysis will vary depending on the
preferred implementation and a wide range of options are
envisaged.
[0447] When performing fluid level measurements, alternating
electrical current signals are applied to the subject via a pair of
microstructures, with resulting voltage signals being measured via
the same microstructures. The magnitude and phase of the applied
current and resulting voltage can then be used to calculate an
impedance value, which depends on fluid levels within the subject.
Accordingly, the measured impedance value can be correlated with a
fluid level, allowing a subject hydration to be determined, and an
example of this will be described in more detail below.
[0448] It will further be appreciated that different information
can be derived depending on the frequency at which measurements are
performed. For example, the system can use Bioimpedance Analysis
(BIA) in which a single low frequency signal is injected into the
subject S, with the measured impedance being used directly in the
determination of biological parameters. In one example, the applied
signal has a relatively low frequency, such as below 100 kHz, more
typically below 50 kHz and more preferably below 10 kHz. In this
instance, such low frequency signals can be used as an estimate of
the impedance at zero applied frequency, which are indicative of
extracellular fluid levels.
[0449] Alternatively, the applied signal can have a relatively high
frequency, such as above 200 kHz, and more typically above 500 kHz,
or 1000 kHz. In this instance, such high frequency signals can be
used as an estimate of the impedance at infinite applied frequency,
which is in turn indicative of a combination of the extracellular
and intracellular fluid levels.
[0450] Alternatively, and/or additionally, the system can use
Bioimpedance Spectroscopy (BIS) in which impedance measurements are
performed at multiple frequencies, which can then be used to derive
information regarding both intracellular and extracellular fluid
levels, for example by fitting measured impedance values to a Cole
model.
[0451] When performing analyte level or concentration measurements,
alternating electrical stimulation signals are applied to the
subject via a pair of microstructures, with resulting electrical
response signals being measured via the same microstructures. The
magnitude and/or phase of the applied signals and resulting
response signals voltage can then be used to calculate an impedance
or capacitance value, which depends on analyte level or
concentration within the subject. Accordingly, the measured
impedance value can be correlated with an analyte level or
concentration, allowing the progression of a disease, disorder or
condition to be monitored or a disease, disorder or condition to be
diagnosed, or the presence, absence, level or concentration of a
medicament, illicit substance or non-illicit substance of abuse, or
chemical warfare agent, poison or toxin to be determined.
[0452] For example, the subject data could be used in conjunction
with previously collected subject data in order to perform a
longitudinal analysis, examining changes in measured values over
time. Additionally and/or alternatively, the subject data could be
analysed using a machine learning model or similar.
[0453] One or more indicators are generated at step 1255, with the
nature of the indicators and the manner in which these are
generated varying depending upon the preferred implementation and
the nature of the analysis being performed.
[0454] At step 1260 data, such as the subject data, the indicators,
or the measurement data, are recorded allowing this to be
subsequently accessed as needed. The indicator may also be provided
to the client device 930 and/or monitoring device 920, allowing
this to be displayed.
[0455] In one example, monitoring devices are allocated to
respective users, with this allocation being used to track
measurements for the subject. An example of a process for
allocating a monitoring device 920 to a subject will now be
described with reference to FIG. 13.
[0456] In this example, the subject initially undergoes an
assessment at step 1300, with this process being performed by a
clinician. The clinician will use the assessment to guide the type
of monitoring that needs to be performed, for example to identify
particular biomarkers that are to be measured, which in turn may
depend on any symptoms or medical diseases, disorders or conditions
suffered by the subject. As part of this process, the clinician
will typically acquire subject attributes at step 1310, such as
measurement of weight, height, age, sex, details of medical
interventions, or the like. This can be performed using a
combination or techniques, such as querying a medical record,
asking questions, performing measurements or the like.
[0457] Once the assessment has been completed, a monitoring device
type can be selected at 1320, with this being performed based on
the measurements that are required. In this regard, it will be
appreciated that different combinations of microstructure
arrangement and sensing modalities can be used in order to allow a
range of different measurements to be performed, and it is
therefore important that the correct selection is made to enable
the measurements to be collected. A specific monitoring device 920
is then allocated to the subject at step 1330. In this regard, in
each device will typically include a unique identifier, such as a
MAC (Media Access Control) address or other identifier, which can
be used to uniquely associate the monitoring device with the
subject.
[0458] At step 1340 the monitoring device 920 can optionally be
configured, for example to update firmware or the instruction set
needed to perform the respective measurements. At step 1350, a
subject record is created, which is used to store details
associated with the subject, including subject attributes, subject
data, indicators, or any other relevant information. Additionally,
the subject record will also typically include an indication of the
monitoring device identifier, thereby associating the monitoring
device with the subject.
[0459] An example of the process of using the device to perform
measurements will now be described with reference to FIGS. 14A and
14B.
[0460] In this example, at step 1400 one or more measurements are
performed. The measurements are performed by utilising the process
described above, for example by having the monitoring device apply
stimulatory signals and measure response signals. Measurement data
is recorded based on the response signals with this being uploaded
to the client device 930 at step 1405, allowing the client device
930 to generate subject data at step 1410. The subject data could
simply be the measurement data, but may also include additional
information provided by the client device 930. This allows user
inputs to be provided via the client device 930, for example
providing details of symptoms, changes in attributes or the like.
The subject data is then uploaded to the server 910 at step 1415.
The server 910 then retrieves one more subject attributes at step
1420, for example from the subject record, with the server 910 then
calculating one or more metrics at step 1425.
[0461] At step 1430, the server 910 analyses the metrics. The
manner in which this is performed will vary depending on the
preferred implementation. For example, this could be achieved by
applying the metrics to a computational model that embodies a
relationship between a relevant health status and the one or more
metrics. Alternatively, the metrics could be compared to defined
thresholds, which can be established from a population of reference
subjects, and which are used to represent certain diseases,
disorders or conditions, such as the presence or absence of a
medical condition. As a further option, the metrics could be
compared to previous metrics for the subject, for example to
examine changes in the metrics, which could in turn represent a
change in health status. The results of the analysis can be used to
generate one or more indicators at step 1435. In one example, the
indicator can be in the form of a score representing a health
status, or could be indicative of a presence, absence or degree of
diseases, disorders or condition.
[0462] At step 1440 the indicator can be stored, with an indication
of the indicator being transferred to the client device 930 at step
1445, allowing the indicator to be displayed, either by the client
device 930 or the monitoring device 920 at step 1450.
[0463] Additionally, and/or alternatively, at step 1455 the
indicator can be used to determine if an action is required, for
example if an intervention should be performed. The assessment of
whether an action is required could be performed in any one of a
number of manners, but typically involves comparing the indicator
to assessment criteria defining a predetermined threshold or range
of acceptable indicator values. For example, comparing a hydration
indicator to a range indicative of normal hydration, or comparing
an analyte indicator indicative of a normal level or concentration
of analytes.
[0464] The assessment criteria can also specify the action required
if the indicator falls outside of the acceptable range, and any
steps required to perform the action, allowing the action to be
performed at step 1460. For example, in a theranostic application,
this could involve causing the applying monitoring device to apply
a stimulation signal to electrodes, thereby allowing one or more
therapeutic agents to be released. Alternatively, if the subject is
dehydrated, the action could include having the monitoring device
provide a recommendation to the user to hydrate, whereas if certain
analytes are detected, this could be indicative of a medical
situation, in which the processing system or monitoring device
could generate a notification which is provided to a clinician, or
other nominated person or system, allowing them to be alerted. The
notification could include any determined indicator and/or measured
response signals, allowing the clinician to rapidly identify any
interventions needed. In a theranostic application, the action
could involve causing the applying monitoring device to apply a
stimulation signal to electrodes, thereby allowing one or more
therapeutic agents to be released. This could be performed in
accordance with a dosing regime, which could be specified as part
of the assessment criteria or defined manually by a clinician, for
example in response to a notification provided as described above.
Alternatively, the action could involve notifying the user, so for
example, if the subject is dehydrated, the action could include
having the monitoring device provide a recommendation to the user
to hydrate.
[0465] It will therefore be appreciated that this enables actions
to be triggered as needed.
[0466] The above described processes describe transfer of data to
remote systems for analysis, which can have a number of benefits.
For example, this allows more complex analysis to be performed than
would otherwise be the case with existing processing capabilities.
This also allows remote oversight, for example, allowing a
clinician to access records associated with multiple patients, in
real-time, enabling the clinician to respond rapidly as needed. For
example, in the event that measured data shows an indication of a
deleterious health state, the clinician could be alerted or
notified, allowing an intervention to be triggered. Additionally,
collective monitoring provides public health benefits, for example
to allow tracking of infectious diseases or similar. Furthermore,
central analysis allows data mining to be used in order refine
analysis processes, making this more accurate as more data is
collected.
[0467] However, it will be appreciated that the distributed
implementation is not essential, and additionally or alternatively,
analysis could be performed in situ, for example, by having the
monitoring device 920 and/or client device 930 perform steps 1425
to 1460 with resulting information being displayed locally, for
example, using the client device 930 or a in-built display.
[0468] A further example of a microstructure arrangement and
analysis technique will now be described with reference to FIGS.
15A to 15F.
[0469] In this example, a patch 1510 is provided, including a
substrate 1511 having a number of microstructures 512 thereon. The
form and configuration of the microstructures is not critical for
the purpose of this example, and it will be appreciated that a
range of different configurations could be used, as described
above.
[0470] In this example, the substrate 1511 includes a substrate
coil 1515, positioned on the substrate 1511, typically on a rear
surface. The coil is operatively coupled to the one or more
microstructure electrodes, which could be electrodes provided on
microstructures, or conductive microstructures themselves.
Typically the substrate coil includes two ends, with each end being
coupled to different microstructure electrodes, as shown by the
dotted lines, so that a signal in the substrate coil 1511 is
applied between the microstructure electrodes. An excitation and
receiving coil (not shown) is provided, typically in a housing of a
measuring device, so that the excitation and receiving coil is
aligned with and placed in proximity to the substrate coil when a
measurement is to be performed, for example, when the housing is
attached to the substrate. This is performed to inductively couple
the excitation and receiving coil to the substrate coil, so that
when an excitation signal is applied to the excitation and
receiving coil by the signal generator, this induces a
corresponding signal in the substrate coil 1515, which is then
applied across the microstructure electrodes.
[0471] The tissue and/or fluid surrounding the microstructure
electrodes, and the electrodes, act as capacitors, as shown. As a
result, the excitation and receiving coil and the substrate coil
act as a tuned circuit, and an example circuit configuration is
shown in FIG. 15B. This includes a fixed inductance 1561 and
capacitance 1562 and resistance 1563, representing the inherent
responsiveness of the excitation and substrate coils. The circuit
also includes a variable capacitance and variable resistance 1565,
1564, representing the responsiveness of the microstructure
electrodes, and the tissue or other materials between the
electrodes. Thus, it will be appreciated that the frequency
response and damping (Q) of the tuned circuit will vary depending
on the values of the variable capacitance and resistance, which in
turn depends on the environment within which the microstructure
electrodes are present.
[0472] In general, when a signal is applied to the excitation and
receiving coil, the overall response will be a constant amplitude
signal in the excitation and receiving coil, as shown in FIG. 15C.
When the drive signal is halted, the circuit will continue to
resonant, with the resulting signal decaying over time as shown to
the right of the dotted line. The rate and/or frequency of the
decay depends on the values of the variable capacitance and
resistance, so different responses 1581, 1582 will arise depending
on conditions within the subject, which in turn allows information
regarding conditions within the subject to be derived. For example,
this can be influenced by binding of analytes to the microstructure
electrode, fluid levels, or the like, so examining changes in the
decay rate and frequency can be used to derive information
regarding the presence of analytes, fluid levels, or the like.
[0473] However, as decay signals are transient, in another example
the circuit's response at different frequencies is analysed and
used to determine the resonant frequency and Q factor of the tuned
circuit, which are in turn indicative of the resistance and
capacitance values. In this regard, a change in electrical
conditions within the subject will result in a change in the
frequency response, as shown in FIG. 15D. For example, a response
in absence of analytes might be as shown in solid lines, whereas
the presence of analytes might result in an increase or decrease in
the resonant frequency and/or Q factor, as shown in dotted
lines.
[0474] In one particular example, in order to be able to more
accurately interpret the response, it is preferable to provide a
control reference. An example of this is shown in FIG. 15E, in
which two patches 1510.1, 1510.2, are provided, each having a
respective substrate 1511 microstructures 1512 and substrate coils
1515. In this example, the patch 1510.2 is coated with a binding
agent to attract analytes of interest, whilst the patch 1510.1 is
uncoated and acts as a control.
[0475] In this case, each substrate coil is driven and alterations,
including attenuation and/or frequency or phase changes of the
signal are measured, which will depend on the resonant frequency
and Q factor. Example altered drive signals are shown in FIG. 15F,
with the signals 1571 representing a control obtain for the patch
1510.2, and the signals 1571.11, 1571.12 and 1571.21, 1571.22
representing different response obtained for the patch 1510.2,
respectively. In this regard, the signals 1571.11, 1571.21
represent applied signals with no analytes, highlighting how
different patches can have different tuned frequency responses, and
with the signals 1571.12, 1571.22, showing changes in frequency
.delta..sub.1, .delta..sub.2, which highlight how different
responses can be measured, which can in turn be used to derive
information regarding the level or concentration of analytes in the
vicinity of the microstructures of the second patch 1510.2.
[0476] The measurement of the changes in frequency occurring in
response to different analyte levels or concentrations may also be
performed in the frequency domain by use of a return-loss-bridge
circuit in the excitation coil. In this manner, the absorption of
rf electromagnetic signal while being swept over a range of
frequencies will show a signal loss in decibels (dB) at the
resonant frequency of the substrate coil. The frequency and depth
of this absorption will be indicative of the analyte level or
concentration.
[0477] It will be appreciated that this technique employs a patch
with no electronically active sensing elements, whilst allowing
measurements to be made regarding conditions within the subject,
such as the presence, absence, level or concentration of analytes
to be easily determined. It will also be appreciated that suitably
adapting the coating allows a range of different analytes to be
sensed and that this can also be adapted for performing other
suitable measurements.
[0478] Further details exemplifying the above described
arrangements will now be described. Manufacture
[0479] Example process for manufacturing a substrate including
microstructures will now be described in more detail.
[0480] In a first example, shown in FIGS. 16A to 16P,
microstructures are made from an insulating polymer applied to a
substrate, with electrodes patterned on the substrate through
selective etching to act acting as electrical connections for the
polymer microstructures. It will be also be appreciated that
conductive polymers could be used, for example through suitable
doping of an insulating polymer.
[0481] In this example, a first step shown in FIGS. 16A to 16G is
to selectively pattern an electrode architecture onto a flexible
polyethylene terephthalate (PET) substrate 1601. An electrode
design, upon which microstructures were to be defined, was
patterned on the PET; in this case Indium Tin Oxide (ITO) 1602
layer deposited atop flexible PET substrate, and the electrode
pattern selectively etched from the ITO layer. The substrate was
prepared (FIG. 16A), before a positive photoresist, AZ1518
(MicroChemicals), was patterned on top of the ITO via
photolithography (FIG. 16B), and soft baked (FIG. 16C). The
photoresist is selectively exposed to UV (FIG. 16D) to define an
electrode pattern, before the photoresist is baked and developed
using a developer AZ 726MIF (MicroChemicals) (FIG. 16E) and the
exposed ITO regions wet acid etched (FIG. 16F). The photoresist was
removed to reveal the final etched ITO pattern that provides the
conductive electrodes for the device (FIG. 16G).
[0482] In a second step, shown in FIGS. 16H to 16P, 3D
microstructures were fabricated from photosensitive polymers onto
the ITO electrodes. The patterned PET substrate with ITO electrodes
was treated with an oxygen plasma (FIG. 16H), to improve wetting
and resist adhesion, and a seed adhesion layer of SU-8 3005
(MicroChemicals) 1604 was spin-coated on to the ITO-PET substrate
(FIG. 161). After baking of the seed SU-8 layer lamination (FIG.
16J) an SUEX SU-8 film resist 1605 (DJ MicroLaminates) was bonded
to the substrate (FIG. 16K) through thermal lamination. After
alignment and exposure to UV through a mask aligner (FIG. 16L), the
exposed SU-8 areas crosslinked to form rows of rectangular
microstructures 1606 with vertical wall profile along the
conductive ITO fingers 1602 (FIG. 16M). The structures are baked,
with the SU-8 1604 and SUEX 1605 before being developed in PGMEA
(Propylene glycol monomethyl ether acetate) (Sigma Aldrich), and
then hard baked (FIG. 16N). A shadow mask 1608 is applied to the
substrate 1601 with the microstructures 1606 being coated with gold
1607 (FIG. 16O) through selective deposition, before the mask is
removed (FIG. 16P), leaving selectively metallized microstructures
that act as electrodes.
[0483] In this example the microstructures have flat tips, but it
will be appreciated that other UV lithography techniques such as
greyscale lithography, backside diffraction lithography, 2 photon
lithography etc. could be employed to define tapered
microstructures.
[0484] Resulting microstructures are shown in FIGS. 17A to 17D.
[0485] In a second example, shown in FIGS. 18A to 18L,
microstructures are made by molding.
[0486] In this example, a silicon wafer 1801 was deposited with a
90 nm layer 1802 of Nitride (FIG. 18A). AZ1505 (MicroChemicals)
positive resist 1803 was then spun on at 4000 rpm (FIG. 18B).
Rectangular pattern to define the blade outline was directly
written using a mask writer 1804 (FIG. 18C). The written pattern
was developed using AZ 726 MIF (MicroChemicals) for 30 secs (FIG.
18D). Reactive ion etching is used to remove the nitride layer 1802
(FIG. 18F), before the photoresist 1813 is removed (FIG. 1818E).
The wafer is then held vertically in a bath of Potassium Hydroxide
at 80.degree. C. for 40 mins, to etch the silicon wafer along the
crystal axis of the wafer (FIG. 18G). The etching stops at the axis
111 thus defining the sharp tips needed, this then acts as a mold
for the devices that are fabricated.
[0487] Omni-Coat is used as a lift off resist and is coated onto
the wafer to a thickness of about 20 nm, using a spin recipe of
3000 RPM for 1 min and then baking at 200.degree. C. for 1 min.
Following this a 5 micron layer 1805 of SU8 3005 is spun on to the
wafer at 3000 RPM following by baking at 65.degree. C. for 1 min,
then at 95.degree. C. for 20 secs followed by 65.degree. C. again
for 1 min (FIG. 18H). The thinner formulation of the SU8 3005 would
allow it to flow more easily into the sharp triangular crevices
etched into the silicon wafer mold. A layer 2016 of SU8 1800 is
then spun on top of this layer to a thickness of 200 microns using
a spin recipe of 2000 RPM for 60 secs (FIG. 181). Following this
the wafer was baked at 65.degree. C. for 5 mins, then at 95.degree.
C. for 35 mins and then again at 65.degree. C. for 5 mins. This
layer of SU8 1800 would allow the sharp tips to stand on a solid
layer.
[0488] Finally the wafer is flood exposed using an Ultra Violet
source 1807 delivering 15 mW/cm.sup.2 of Power for 40 secs (FIG.
18J). The structures are released by soaking the wafer in an AZ 726
developer solution overnight (FIG. 18K) and exposed the wafer to a
thermal shock of 120.degree. C. for 15 secs. The structures are
removed from the mold flipped and dried using Nitrogen gas (FIG.
18L).
[0489] Resulting microstructures are shown in FIGS. 19A and 19B and
19C and 19D.
[0490] FIGS. 20A and 20B show silicon blades fabricated via
etching. FIG. 20A shows the blade coated with a nearly 1 micron
thick layer of SU8 3005 which has been diluted in a ratio of 3:2
using SU8 thinner and spun at 5000 RPM for 40 secs. FIG. 20B gives
a depiction of the blade selectively coated at its base with the
polymer coating. While the tip of the blade is bare and available
for detection purposes only at this area. This selective coating is
achieved by pressing and removing the coated blade in FIG. 20A into
a thin layer of Aluminium foil which mechanically removes the
resist from the tip of the blade. This allows the blade to be
partially covered with an insulative coating, so that only the tip
portion acts as an electrode, thereby allowing measurements to be
performed in the epidermis and/or dermis, as described above with
respect to FIGS. 5J and 5K.
Application
[0491] Vibration applied to a patch, can result in a temporary
change to the mechanical properties of the skin surrounding the
patch, resulting in reduced friction between the microstructures
and skin, increased crack propagation and an decrease in
application force due to a modulation effect caused by the
vibration. As a result of these changing properties a patch applied
with the addition of vibration will penetrate deeper than a patch
without vibration for the same applied force.
[0492] Experiments were conducted to validate this, with forces
ranging from 1.25N to 40N being used to apply a patch into porcine
ear at a quasi-static velocity of 0.83 mm/s. Each force was tested
with and without vibration, with the patch being applied to the
tissue for 10 seconds under load, before then being removed in each
case. The mechanism of vibration was a z-axis vibration motor run
at 6.6Vpp and 180 Hz resulting in a vibration amplitude of 30 um.
Once testing was complete each test site was removed from the ear
and examined via H&E staining.
[0493] Observing the results below for the penetration of a patch
at 2.5N with and without vibration there is evidence to suggest an
increase in penetration depth with the addition of vibration. Of
the 6 penetration sites extracted from one row of microarray
structures without vibration, all 6 blades were able to penetrate
the stratum corneum while only 1 microstructure was able to
penetrate the epidermis. In contrast, of the 5 penetration sites
extracted from the sample with vibration, there is clear and
significant penetration for 3 of the microstructures. Considering
this, there is evidence to suggest that the addition of vibration
will increase penetration depth of the patch for the same forces
than for patch without.
[0494] FIG. 21A to 21F are images demonstrating penetration of
porcine ear by a microstructure without vibration, with only FIG.
21E demonstrating penetration of the epidermis, whereas FIG. 21G to
21K are images demonstrating penetration of porcine ear by a
microstructure with vibration, with FIGS. 21H, 21I, 21K
demonstrating penetration of the epidermis.
[0495] In further experiment, immediately after a patch is applied
to tissue, and then removed, an aqueous solution of Methylene Blue
(1% v/v) was applied to the site and removed. As shown in FIG. 22A
to 22D, which shows results for patches having a microstructure
density of 188 per cm.sup.2, 300 per cm.sup.2, 550 per cm.sup.2,
the blue die selectively stains the sites at which the stratum
corneum is penetrated and demonstrates microstructures penetration
across the patch.
[0496] In a further example, a penetration test was performed for
microstructures with different configurations and different
application forces. In this example, a microstructure density was
188 per cm.sup.2. The force is applied with a handheld force gauge,
no vibration, with the patch being applied for 10 seconds under
load, before then being removed. For this example, microstructures
in the form of plates were used that included vertical side walls,
similar to those shown in FIGS. 5A and 5B, as well as plates
including shoulders, similar to those shown in FIGS. 5J and 5K.
Results shown in FIG. 23A include microstructures with shoulders at
5N applied force 2301, microstructures with shoulders at 10N
applied force 2302, microstructures with no shoulders at 5N applied
force 2303, microstructures with no shoulders at 10N applied force
2304.
[0497] As shown, all blades are shown to penetrate to a depth of 10
.mu.m at forces of 5N or 10N. With an application force of 5N 60%
of the blades with shoulders penetrate to 50 .mu.m, and zero blades
with shoulders penetrate to 100 .mu.m, compared to 100% and 90% for
blades with vertical sidewalls at 50 .mu.m and 100 .mu.m
respectively.
[0498] With an application force of 10N 100% of the blades
penetrate to 50 .mu.m for both geometries, but only 15% of blades
with shoulders penetrate to 100 .mu.m, compared to 100% for blades
with vertical sidewalls.
[0499] This demonstrates both that only relative low force is
required to apply the microstructures and that the presence of
shoulders can be used to control the extent of penetration into the
epidermis.
[0500] In another experiment, microstructure penetration with
application at a constant force (2.5N), with or without vibration
was compared. Results shown in FIG. 24B demonstrate vibration helps
increase penetration depth.
[0501] Accordingly, the above described arrangement provides a
wearable monitoring device that uses microstructures that breach a
barrier, such as penetrating into the stratum corneum in order to
perform measurements on a subject. The measurements can be of any
appropriate form, and can include measuring the presence of
biomarkers or other analytes within the subject, measuring
electrical signals within the subject, or the like. Measurements
can then be analysed and used to generate an indicator indicative
of a health status of the subject.
[0502] In one example, the above described system allows analytes
to be detected in specific tissue sites in the skin, in situ. The
microstructures can be coated with a reagent or binding agent,
allowing analytes within the subject to react with or bind to the
microstructures in turn allowing these to be detected using
suitable optical or electrical measurement techniques. The coatings
can be specifically designed to capture analytes with extremely
high specificity. Such specificity allows specific analytes of
interest to be detected without the need for purification or
complex chemical analysis.
[0503] The length of the structures can be controlled during
manufacture to enable targeting of specific layers in the target
tissue. In one example, this is performed to target analytes in the
epidermal and/or dermal ISF, although analytes in capillary blood
can also be targeted.
[0504] Specific probes can be localized to individual structures or
areas of structures, so that multiple targets can be analysed in a
single assay simply by their location in a 2-dimensional array.
This could facilitate the analysis of disease-specific analyte
panels to increase the sensitivity/specificity of the diagnostic
results.
[0505] The patches can therefore provide a measurement device which
overcomes the need for traditional blood or ISF samples to be taken
for diagnostic purposes representing an opportunity for a clinician
to diagnose and avoid time and processing costs at centralised
testing facilities. It may also open new markets since diagnostic
equipment and blood sampling expertise is not needed e.g. in
developing countries, `in-field` military applications, medical
countermeasures, emergency and triage.
[0506] This allows patches to be used as a non-invasive, pain-free
measurement platform that can measure analytes in situ. The type of
material detected by the patch may be controlled by the length of
the structures, such that ISF can be targeted specifically. This
embodiment does not include a specific analysis type; a number of
established techniques can be used for fluid analysis including,
but not limited to, mass spectrometry, microarrays, DNA/protein
sequencing, HPLC, ELISA, Western Blots and other gel methods,
etc.
[0507] Using affinity surface coatings on each structure allow a
reduction of non-specific adsorption of ISF components whilst
facilitating specific extraction of the molecular targets of
interest.
[0508] By arranging the structures in a two-dimensional format,
multiple probes can be attached to the same patch, with the results
from the sandwich assay decoded based on the 2-D array position of
the individual structures. This essentially allows array-style
processing without the need for sample extraction, purification,
labelling, etc.
Erythema
[0509] Studies have been performed to evaluate the tolerability and
functionality of microstructure patches in humans.
[0510] In one example, a qualitative tolerability assessment was
performed following microstructure patches application which noted
a very mild local response at the application site immediately
post-removal. This was characterized by slight indentation with no
overt erythema or oedema, which was resolved within 15 minutes of
removal. This is shown in FIG. 39A. This shows the indentation was
most prominent around the edges and corners of the microstructure
patch, with very mild redness at these locations, and with no
redness associated with the microstructures themselves.
[0511] Scanning Electron Microscopy (SEM) was performed to confirm
that the microstructures had, in fact, penetrated the skin, showing
cellular debris remaining on the removed microstructures, as shown
in FIG. 39B, confirming successful microstructure penetration
despite the absence of overt erythema.
[0512] To investigate this observation further, we two dedicated
erythema studies were performed with multiple subjects. These
studies investigated the local skin response to microstructure
patch application to the skin of the anterior forearm over a time
period of 2 hours. Microstructure patches were applied using a
guided load cell mechanism, at a force of either 5N remaining in
place for 30 minutes (Study 1) or 3N and remaining in place for 10
minutes (Study 2).
[0513] The first human erythema study was on five volunteers. In
some cases, hair was removed from the skin using depilatory cream
and a paper mask was fixed to the application area to avoid any
effect due to sensitivity to surgical adhesives in tapes. Three
separate non-functionalised microstructure patches were applied to
skin exposed by windows in the paper mask, and a fourth window was
untreated and used as a control for comparison.
[0514] Observations were made for local erythema and a scoring
rubric was used as given in Table 5 below.
TABLE-US-00005 TABLE 5 eScore Observation 0 No discernable
difference relative to control 1 Very mild redness 2 Mild redness 3
Red region extending beyond 4 mm.sup.2 application area 4 Extensive
redness and/or capillary rupture 5 Frank blood and/or oedema
superficially
[0515] Results from the first study are shown in FIG. 40A, which
shows the eScores for Subjects 01-05 in this study, which were
independently assessed at 10, 20, 30, 60 and 120 minutes
post-application. Data points represent the average eScore from
three Microwearables per subject per timepoint.
[0516] Results show that all volunteers experienced some mild or
very mild erythema at the site of Microwearable application as
observed immediately after removal, which quickly resolved within
60 minutes. No erythema was noted after this time point. Similar to
the earlier single subject observation, the indentation/redness was
localised around the edges of the Microwearable, with little or no
effect seem from the microstructures themselves.
[0517] The second erythema study was performed on three volunteers.
Two Microwearable devices were applied at 3N and were removed after
10 minutes of wearing. To investigate further the `edge effect`
observed in a first-in-human trial and in Study 1, a flat patch
(i.e. without microstructures) was applied on the third skin site,
for comparison. The fourth window remained untreated as a control.
Results are shown in FIG. 40B, which shows the eScore observations
(data points are an average of 2 separate observations per subject
per time point) over 120 minutes post-removal.
[0518] Results are similar to Study 1 in that no subject
experienced erythema more extensive than `mild redness` at the site
immediately prior to removal of the Microwearable. This mild
erythema resolved quickly within 60 minutes, with one subject with
a score of 0.5 at 60 minutes, which subsequently resolved
completely by 120 minutes. No erythema was observed following
application of flat patches, which may suggest that the very
mild/mild erythema observed following microstructure patch
application is associated with skin barrier penetration (i.e. by
the presence of microstructures).
[0519] Microstructure patch eScores were, in general, lower in
Study 2 than Study 1, suggesting that lowering the application
force of application reduces the extent of the mild erythema that
occurs. As the erythema was observed immediately after the
microstructure patches were removed and did not increase over time,
it appears erythema is caused by the application event
itself--driven by the corners and edges of the microstructure
patches--and is not exacerbated by continuous wearing.
Future-generation microstructure patch can use different edges and
corner configurations leading to negligible erythema.
[0520] As no local erythema was observed within the area covered by
microstructures, SEM was performed to confirm that the structures
had successfully penetrated the skin of the subjects in Study 1.
Example images of individual or row of microstructures after
application to two subjects are shown in FIG. 41, including images
of individual microstructures prior to application to the skin
(FIGS. 41A and 41D) and images post application (FIGS. 41B, 41C and
41E, 41F).
[0521] Images from all subjects confirmed successful penetration of
the skin, from the presence of biological material located on the
upper portion of the microstructures (FIGS. 41B and 41E), with
arrows indicating examples of cellular debris extracted by the
microstructures on removal.
[0522] FIGS. 41C and 41F show rows of microstructures, and exhibit
areas with dried interstitial fluid as indicated by the arrows.
These observations confirm that the microstructures have
successfully breached the outermost stratum corneum layer of the
skin and are able to access cellular environments beneath to gain
access to the interstitial fluid, which is the source of
bio-signals including biomarkers of disease.
[0523] It is therefore apparent that microstructure patches are at
worst only associated with very mild/mild erythema at the site of
application. This mild local response is transient, and is
completely resolved within 60-120 mins post-application. Any
redness immediately occurs after application, and is not associated
with continuous wearing of the microstructure patch.
[0524] Any erythema is focused around the edges and corners of the
microstructure patch, with little/no erythema noted in the area
covered by microstructures, but the observation that a flat patch
had no effect suggests that the erythema after microstructure patch
application is associated with a physical breach of the skin
barrier.
[0525] Despite the observation that microstructures did not cause
overt erythema, it was we confirmed that microstructure penetration
was successful, with visible breaching of the stratum corneum and
with confirmed access to skin compartments rich in interstitial
fluid.
Use of the System
[0526] The system of the invention may be used to determine the
presence, absence, level or concentration of one or more analytes
in a wide range of applications as discussed herein, including,
diagnosing or monitoring the progression of a disease, disorder or
condition in a subject; the presence, absence, level or
concentration of an illicit substance or non-illicit substance, or
a chemical warfare agent, poison or toxin, or the level or
concentration of a medicament.
[0527] Accordingly, in a further aspect, there is provided a method
for diagnosing or monitoring the progression of a disease, disorder
or condition in a subject, comprising determining the presence,
absence, level or concentration of one or more analytes in the
viable epidermis and/or dermis of the subject using the system of
the invention, and determining the presence, absence and/or
progression of the disease, disorder or condition based on whether
the one or more analytes is present or absent, or whether the level
or concentration of the one or more analytes is above or below a
corresponding predetermined threshold that correlates with the
presence, absence or progression of the disease, disorder or
condition.
[0528] The invention also provides the use of the system of the
invention for diagnosing or monitoring the progression of a
disease, disorder or condition in a subject. There is further
provided the system of the invention for use in diagnosing or
monitoring the progression of a disease, disorder or condition in a
subject. In particular embodiments of any one of the above aspects,
the system determines the presence, absence, level or concentration
of one or more analytes in the viable epidermis and/or dermis of
the subject and the presence, absence and/or progression of the
disease, disorder or condition is determined based on whether the
one or more analytes is present or absent, or whether the level or
concentration of the one or more analytes is above or below a
corresponding predetermined threshold that correlates with the
presence, absence or progression of the disease, disorder or
condition.
[0529] Suitable diseases, disorders or conditions, analytes and
exemplary concentration levels are discussed supra.
[0530] In some embodiments, the disease, disorder or condition is
selected from cardiac damage, myocardial infarction and acute
coronary syndrome, and the one or more analytes is troponin or a
subunit thereof. In particular embodiments, the one or more
analytes is troponin I.
[0531] In another aspect, there is provided a method of treating a
disease, disorder or condition in a subject comprising determining
the presence, absence, level or concentration of one or more
analytes in the viable epidermis and/or dermis of the subject using
the system of the invention, determining the presence or
progression of the disease, disorder or condition based on whether
the one or more analytes is present, or whether the level or
concentration of the one or more analytes is above or below a
corresponding predetermined threshold that correlates with the
presence or progression of the disease, disorder or condition, and
administering a treatment for the disease, disorder or
condition.
[0532] In a further aspect, there is provided a method of treating
a disease, disorder or condition in a subject comprising exposing
the subject to a treatment regimen for treating the disease,
disorder or condition based on an indicator obtained from an
indicator-determining method, said indicator-determining method
comprising determining the presence, absence, level or
concentration of one or more analytes in the viable epidermis
and/or dermis of the subject using the system of the invention, and
determining the presence or progression of the disease, disorder or
condition based on whether the one or more analytes is present, or
whether the level or concentration of the one or more analytes is
above or below a corresponding predetermined threshold that
correlates with the presence or progression of the disease,
disorder or condition.
[0533] In a related aspect, the present invention provides a method
for managing a disease, disorder or condition in a subject
comprising exposing the subject to a treatment regimen for treating
the disease, disorder or condition based on an indicator obtained
from an indicator-determining method, said indicator-determining
method comprising determining the presence, absence, level or
concentration of one or more analytes in the viable epidermis
and/or dermis of the subject using the system of the invention, and
determining the presence or progression of the disease, disorder or
condition based on whether the one or more analytes is present, or
whether the level or concentration of the one or more analytes is
above or below a corresponding predetermined threshold that
correlates with the presence or progression of the disease,
disorder or condition.
[0534] In any one of the above aspects, the predetermined threshold
represents a level or concentration of the analyte in a
corresponding sample from a control subject (e.g. in the viable
epidermis and/or dermis of the control subject), or represents a
level or concentration above or below the level or concentration of
the analyte in a corresponding sample from a control subject, and
levels or concentrations above or below said threshold indicates
the presence, absence or progression of a disease, disorder or
condition. The control subject may be a subject who does not have
the disease, disorder or condition; a subject who does have the
disease, disorder or condition; or a subject who has a particular
stage or severity of the disease, disorder or condition. When
progression of the disease, disorder or condition is being
monitored, the predetermined threshold may be a level or
concentration of the analyte in a sample from the same subject
taken at an earlier time (e.g. several minutes, hours, days, weeks
or months earlier), and an increase or decrease in the analyte
level or concentration may indicate the progression or regression
of the disease, disorder or condition.
[0535] Suitable treatments for the disease, disorders or conditions
discussed supra are well known in the art, and a skilled person
will readily be able to select an appropriate treatment. For
example, suitable disorders and exemplary treatments include, but
are not limited to, renal failure and treatment with dialysis, a
kidney transplant, an angiotensin-converting enzyme inhibitor (e.g.
benazepril, zofenopril, perindopril, trandolapril, captopril,
enalapril, lisinopril or ramipril), an angiotensin II receptor
blocker (e.g. losartan, irbesartan, valsartan, candesartan,
telmisartan or fimasartan), a diuretic (e.g. furosemide,
bumetanide, ethacrynic acid, torsemide, chlorothiazide,
hydrochlorothiazide, bendroflumethiazide or trichlormethiazide), a
statin (e.g. atorvastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin or simvastatin), calcium,
glucose or sodium polystyrene sulfonate, and/or a calcium infusion;
cardiac failure and treatment with an angiotensin-converting enzyme
inhibitor (e.g. benazepril, zofenopril, perindopril, trandolapril,
captopril, enalapril, lisinopril or ramipril), an angiotensin II
receptor blocker (e.g. losartan, irbesartan, valsartan,
candesartan, telmisartan or fimasartan), a diuretic (e.g.
furosemide, bumetanide, ethacrynic acid, torsemide, chlorothiazide,
hydrochlorothiazide, bendroflumethiazide or trichlormethiazide), a
beta blocker (e.g. carvedilol, metoprolol or bisoprolol), an
aldosterone antagonist (e.g. spironolactone or eplerenone), and/or
an inotrope (e.g. digoxin, berberine, levosimendan, calcium,
dopamine, dobutamine, dopexamine, epinephrine, isoprenaline,
norepinephrine, angiotensin II, enoximone, milrinone, amrinone,
theophylline, glucagon or insulin); essential hypertension and
treatment with a beta blocker (e.g. carvedilol, metoprolol or
bisoprolol), a calcium channel blocker (e.g. amlodipine,
felodipine, isradipine, nicardipine, nifedipine, nimodipine or
nitrendipine), a diuretic (e.g. furosemide, bumetanide, ethacrynic
acid, torsemide, chlorothiazide, hydrochlorothiazide,
bendroflumethiazide or trichlormethiazide), angiotensin-converting
enzyme inhibitor (e.g. benazepril, zofenopril, perindopril,
trandolapril, captopril, enalapril, lisinopril or ramipril), an
angiotensin II receptor blocker (e.g. losartan, irbesartan,
valsartan, candesartan, telmisartan or fimasartan), and/or a renin
inhibitor (e.g. aliskiren); bacterial infection and treatment with
antibiotics (e.g. quinolones (e.g. amifloxacin, cinoxacin,
ciprofloxacin, enoxacin, fleroxacin, flumequine, lomefloxacin,
nalidixic acid, norfloxacin, ofloxacin, levofloxacin, lomefloxacin,
oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin,
sparfloxacin, clinafloxacin, gatifloxacin, moxifloxacin,
gemifloxacin, or garenoxacin), tetracyclines, glycylcyclines or
oxazolidinones (e.g. chlortetracycline, demeclocycline,
doxycycline, lymecycline, methacycline, minocycline,
oxytetracycline, tetracycline, tigecycline, linezolide or
eperezolid), aminoglycosides (e.g. amikacin, arbekacin, butirosin,
dibekacin, fortimicins, gentamicin, kanamycin, menomycin,
netilmicin, ribostamycin, sisomicin, spectinomycin, streptomycin or
tobramycin), .beta.-lactams (e.g. imipenem, meropenem, biapenem,
cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone,
cefazolin, cefixime, cefmenoxime, cefodizime, cefonicid,
cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole,
cefpiramide, cefpodoxime, cefsulodin, ceftazidime, cefteram,
ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
cefuzonam, cephacetrile, cephalexin, cephaloglycin, cephaloridine,
cephalothin, cephapirin, cephradine, cefinetazole, cefoxitin,
cefotetan, azthreonam, carumonam, flomoxef, moxalactam,
amdinocillin, amoxicillin, ampicillin, azlocillin, carbenicillin,
benzylpenicillin, carfecillin, cloxacillin, dicloxacillin,
methicillin, mezlocillin, nafcillin, oxacillin, penicillin G,
piperacillin, sulbenicillin, temocillin, ticarcillin, cefditoren,
cefdinir, ceftibuten or cefozopran), rifamycins, macrolides (e.g.
azithromycin, clarithromycin, erythromycin, oleandomycin,
rokitamycin, rosaramicin, roxithromycin or troleandomycin),
ketolides (e.g. telithromycin or cethromycin), coumermycins,
lincosamides (e.g. clindamycin or lincomycin) or chloramphenicol);
viral infection and treatment with antivirals (e.g. abacavir
sulfate, acyclovir sodium, amantadine hydrochloride, amprenavir,
cidofovir, delavirdine mesylate, didanosine, efavirenz,
famciclovir, fomivirsen sodium, foscarnet sodium, ganciclovir,
indinavir sulfate, lamivudine, lamivudine/zidovudine, nelfinavir
mesylate, nevirapine, oseltamivir phosphate, ribavirin, rimantadine
hydrochloride, ritonavir, saquinavir, saquinavir mesylate,
stavudine, valacyclovir hydrochloride, zalcitabine, zanamivir or
zidovudine); autoimmune disorders and treatment with
immunosuppressants (e.g. prednisone, dexamethasone, hydrocortisone,
budesonide, prednisolone, tofacitinib, cyclosporine,
cyclophosphamide, nitrosoureas, platinum compounds, methotrexate,
azathioprine, mercaptopurine, fluorouracil, dactinomycin,
anthracyclines, mitomycin C, bleomycin, mithramycin, antithymocyte
globulin, thymoglobulin, Muromonab-CD3, basiliximab, daclizumab,
tacrolimus, sirolimus, everolimus, infliximab, etanercept,
mycophenolic acid or mycophenolate, fingolimod, azathioprine,
leflunomide, abatacept, adalimumab, anakinra, certolizumab,
golimumab, ixekizumab, natalizumab, rituximab, secukinumab,
toclizumab, ustekinumab, vedolizumab or myriocin) and/or NSAIDs
(e.g. acetylsalicylic acid (aspirin), diclofenac, diflusinal,
etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid,
mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide,
nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,
piroxicam, sulfasalazine, sulindac, tolmetin, zomepirac, celecoxib,
deracoxib, etoricoxib, mavacoxib or parecoxib); rheumatological
disorders and treatment with NSAIDs as described supra, DMARDs
(e.g. methotrexate, hydroxychloroquinone or penicillamine),
prednisone, dexamethasone, hydrocortisone, budesonide,
prednisolone, etanercept, golimumab, infliximab, adalimumab,
anakinra, rituximab, abatacept, and/or other immunosuppressants
described supra; sepsis and antibiotics as described supra,
immunosuppressants as described supra and/or an antihypotensive
agent (e.g. vasopressin, norepinephrine, dopamine or epinephrine);
and pulmonary embolism and treatment with an anticoagulant (e.g.
heparin, warfarin, bivalirudin, dalteparin, enoxaparin, dabigatran,
edoxaban, rivaroxaban, apixaban or fondaparinux) and/or a
thrombolytic/fibrinolytic (e.g. tissue plasminogen activator,
reteplase, streptokinase or tenecteplase).
[0536] In some embodiments, the disease, disorder or condition is
cardiac damage, myocardial infarction or acute coronary syndrome,
the one or more analytes is troponin or a subunit thereof. Suitable
treatments for cardiac damage, myocardial infarction or acute
coronary syndrome may include, but are not limited to, aspirin, an
anticoagulant (e.g. heparin, warfarin, bivalirudin, dalteparin,
enoxaparin dabigatran, edoxaban, rivaroxaban, apixaban or
fondaparinux), a beta-blocker (e.g. carvedilol or metoprolol), a
thrombolytic/fibrinolytic (e.g. tissue plasminogen activator,
reteplase, streptokinase or tenecteplase), an
angiotensin-converting enzyme inhibitor (e.g. benazepril,
zofenopril, perindopril, trandolapril, captopril, enalapril,
lisinopril or ramipril), an angiotensin II receptor blocker (e.g.
losartan, irbesartan, valsartan, candesartan, telmisartan or
fimasartan), a statin (e.g. atorvastatin, fluvastatin, lovastatin,
mevastatin, pitavastatin, pravastatin, rosuvastatin or
simvastatin), an analgesic (e.g. morphine, etc.), nitroglycerin,
and the like, or combinations thereof.
[0537] The invention further contemplates the use of the system of
the invention for determining the presence, absence, level or
concentration of an illicit substance or non-illicit substance of
abuse in a subject. Accordingly, in another aspect, there is
provided a method of determining the presence, absence, level or
concentration of an illicit substance or non-illicit substance of
abuse in a subject, comprising determining the presence, absence,
level or concentration of the illicit substance, non-illicit
substance of abuse or a metabolite thereof in the viable epidermis
and/or dermis of the subject using the system of the invention.
[0538] There is also provided the use of the system of the
invention for determining the presence, absence, level or
concentration of an illicit substance or non-illicit substance of
abuse in a subject, and the system of the invention for use in
determining the presence, absence, level or concentration of an
illicit substance or non-illicit substance of abuse in a subject.
In particular embodiments of any one of these aspects, the system
determines the presence, absence, level or concentration of the
illicit substance, non-illicit substance of abuse or metabolite
thereof in the viable epidermis and/or dermis of the subject.
[0539] Suitable illicit substances are discussed supra and include,
but are not limited to, methamphetamine, amphetamine,
3,4-methylenedioxymethamphetamine (MDMA),
N-ethyl-3,4-methylenedioxyamphetamine (MDEA),
3,4-methylenedioxy-amphetamine (MDA), cannabinoids (e.g.
delta-9-tetrahydrocannabinol,
11-hydroxy-delta-9-tetrahydrocannabinol,
11-nor-9-carboxydelta-9-tetrahydrocannabinol), cocaine,
benzoylecgonine, ecgonine methyl ester, cocaethylene, ketamine, and
the opiates (e.g. heroin, 6-monoacetylmorphine, morphine, codeine,
methadone and dihydrocodeine). Non-limiting non-illicit substances
of abuse include alcohol, nicotine, prescription medicine or over
the counter medicine taken for non-medical reasons, a substance
taken for a medical effect, wherein the consumption has become
excessive or inappropriate (e.g. pain medications, sleep aids,
anti-anxiety medication, methylphenidate, erectile-dysfunction
medications), and the like.
[0540] The invention further contemplates the use of the system of
the invention for determining the presence, absence, level or
concentration of a chemical warfare agent, poison and/or toxin in a
subject. Accordingly, in another aspect, there is provided a method
of determining the presence, absence, level or concentration of a
chemical warfare agent, poison and/or toxin in a subject,
comprising determining the presence, absence, level or
concentration of the chemical warfare agent, poison and/or toxin or
a metabolite thereof in the viable epidermis and/or dermis of the
subject using the system of the invention. In particular
embodiments, the method is for determining the presence, absence,
level or concentration of a chemical warfare agent.
[0541] There is also provided the use of the system of the
invention for determining the presence, absence, level or
concentration of a chemical warfare agent, poison and/or toxin in a
subject, and the system of the invention for use in determining the
presence, absence, level or concentration of a chemical warfare
agent, poison and/or toxin in a subject; especially a chemical
warfare agent. In particular embodiments of any one of these
aspects, the system determines the presence, absence, level or
concentration of the chemical warfare agent, poison and/or toxin or
a metabolite thereof in the viable epidermis and/or dermis of the
subject.
[0542] Suitable chemical warfare agents, poisons and/or toxins are
discussed supra.
[0543] The system of the invention may also be used to determine
and/or monitor the level or concentration of a medicament
administered to a subject, for example, to optimise and/or adjust
the dose of the medicament. The invention provides a method for
determining and/or monitoring the level or concentration of a
medicament administered to a subject, comprising determining the
level or concentration of the medicament or a component or
metabolite thereof in the viable epidermis and/or dermis of the
subject using the system of the invention.
[0544] There is further provided the use of the system of the
invention for determining and/or monitoring the level or
concentration of a medicament administered to a subject, and the
system of the invention for use in determining and/or monitoring
the level or concentration of a medicament administered to a
subject. In particular embodiments, the system of the invention
determines the level or concentration of the medicament or a
component or metabolite thereof in the viable epidermis and/or
dermis of the subject.
[0545] In some embodiments, the dose of the medicament is increased
or decreased following determination of the level or concentration
of the medicament or a component or metabolite thereof.
[0546] In a further aspect, there is provided a method of
monitoring the efficacy of a treatment regimen in a subject with a
disease, disorder or condition, wherein the treatment regimen is
monitored for efficacy towards a desired health state (e.g. absence
of the disease, disorder or condition. Such method generally
comprises determining the presence, absence, level or concentration
of one or more analytes indicative of the efficacy of the treatment
regimen in the viable epidermis and/or dermis of the subject using
the system of the invention after treatment of the subject with the
treatment regimen, and comparing the level or concentration of the
one or more analytes to a reference level or concentration of the
one or more analytes which is correlated with a presence, absence
or stage of the disease, disorder or condition to thereby determine
whether the treatment regimen is effective for changing the health
status of the subject to a desired health state. In some
embodiments, the one or more analytes is a medicament administered
during the treatment regimen, or a component or metabolite
thereof.
[0547] In a related aspect, there is provided a method of
monitoring the efficacy of a treatment regimen in a subject with a
disease, disorder or condition, wherein the treatment regimen is
monitored for efficacy towards a desired health state (e.g. absence
of the disease, disorder or condition). Such method generally
comprises determining an indicator according to an
indicator-determining method, said indicator-determining method
comprising determining the presence, absence, level or
concentration of one or more analytes in the viable epidermis
and/or dermis of the subject using the system of the invention
after treatment of the subject with the treatment regimen, and
assessing the likelihood of the subject having a presence, absence
or stage of a disease, disorder or condition based on whether the
one or more analytes is present, or whether the level or
concentration of the one or more analytes is above or below a
corresponding predetermined threshold that correlates with the
presence, absence or stage of the disease, disorder or condition,
using the indicator to thereby determine whether the treatment
regimen is effective for changing the health status of the subject
to a desired health state. In some embodiments, the one or more
analytes is a medicament administered during the treatment regimen,
or a component or metabolite thereof.
[0548] In some embodiments of any one of the above aspects, the
treatment regimen is adjusted following such methods. Suitable
predetermined thresholds for such aspects are discussed supra.
[0549] The invention also provides the system of the invention for
use in such methods, and the use of the system for such
methods.
[0550] A skilled person will readily appreciate that the system of
the invention may be used to determine and monitor the level or
concentration of a wide range of medicaments and treatment regimens
and will readily be able to use and select suitable medicaments and
treatment regimens. For example, suitable medicaments include, but
are not limited to, cancer therapies, vaccines, analgesics,
antipsychotics, antibiotics, anticoagulants, antidepressants,
antivirals, sedatives, antidiabetics, contraceptives,
immunosuppressants, antifungals, antihelmintics, stimulants,
biological response modifiers, NSAIDs, corticosteroids, DMARDs,
anabolic steroids, antacids, antiarrhythmics, thrombolytics,
anticonvulsants, antidiarrheals, antiemetics, antihistamines,
antihypertensives, anti-inflammatories, antineoplastics,
antipyretics, antivirals, barbiturates, .beta.-blockers,
bronchodilators, cough suppressants, cytotoxics, decongestants,
diuretics, expectorants, hormones, laxatives, muscle relaxants,
vasodilators, tranquilizers and vitamins.
[0551] In particular embodiments, the medicament is one which has a
narrow therapeutic window, such as particular antibiotics (e.g.
aminoglycosides including kanamycin, gentamycin and streptomycin),
anticonvulsants (e.g. carbamazepine and clonazepam), vasodilators,
anticoagulants including heparin and warfarin, digoxin, and the
like. In such embodiments, the methods and uses may further
comprise increasing or decreasing the dose of the medicament
administered to the subject.
[0552] In any one of the above aspects, the methods and uses
further comprise attaching the system of the invention to the skin
of the subject prior to determining the presence, absence, level or
concentration of the one or more analytes. In such embodiments, the
system of the invention breaches a stratum corneum of the
subject.
[0553] The above described patches may also be used to test other
forms of subjects, such as food stuffs, or the like. In this
example, the patch could be used to test for the presence of
unwanted contaminants, such as pathogens, such as bacteria,
exotoxins, mycotoxins, viruses, parasites, or the like, as well as
natural toxins. Additionally contaminants could include
agrochemicals, environmental contaminants, pesticides, carcinogens,
or the like.
[0554] Accordingly, it will be appreciated that the term subject
can include living subjects, such as humans, animals, or plants, as
well as non-living materials, such as foodstuffs, packaging, or the
like.
[0555] Accordingly, the above described arrangement provides a
wearable monitoring device that uses microstructures that breach a
barrier, such as penetrating into the stratum corneum in order to
perform measurements on a subject. The measurements can be of any
appropriate form, and can include measuring the presence of
biomarkers or other analytes within the subject, measuring
electrical signals within the subject, or the like. Measurements
can then be analysed and used to generate an indicator indicative
of a health status of the subject.
[0556] In one example, the above described system allows analytes
to be detected in specific tissue sites in the skin, in situ. The
microstructures can be coated with a material for binding one or
more analytes of interest or may be formed by a binding agent as
described supra, allowing analytes within the subject to bind to
the microstructures in turn allowing these to be detected using
suitable optical or electrical measurement techniques. The coatings
and/or microstructures can be specifically designed to capture
analytes with extremely high specificity. Such specificity allows
specific analytes of interest to be detected without the need for
purification or complex chemical analysis.
[0557] The length of the structures can be controlled during
manufacture to enable targeting of specific layers in the target
tissue. In one example, this is performed to target analytes in the
epidermal and/or dermal layers, although analytes in capillary
blood can also be targeted.
[0558] Specific probes can be localized to individual structures or
areas of structures, so that multiple targets can be analysed in a
single assay simply by their location in a 2-dimensional array.
This could facilitate the analysis of disease-specific analyte
panels to increase the sensitivity/specificity of the diagnostic
results.
[0559] The patches can therefore provide a measurement device which
overcomes the need for traditional blood or ISF samples to be taken
for diagnostic purposes representing an opportunity for a clinician
to diagnose and avoid time and processing costs at centralised
testing facilities. It may also open new markets since diagnostic
equipment and blood sampling expertise is not needed e.g. in
developing countries, `in-field` military applications, medical
countermeasures, emergency and triage.
[0560] This allows patches to be used as a non-invasive, pain-free
measurement platform that can measure analytes in situ. The type of
material detected by the patch may be controlled by the length of
the structures, such that different regions can be targeted
specifically. This embodiment does not include a specific analysis
type; a number of established techniques can be used for fluid
analysis including, but not limited to, mass spectrometry,
microarrays, DNA/protein sequencing, HPLC, ELISA, Western Blots and
other gel methods, etc.
[0561] Using affinity surface coatings on each structure allows a
reduction of non-specific adsorption of substances whilst
facilitating specific extraction of the molecular targets of
interest.
[0562] By arranging the structures in a two-dimensional format,
multiple probes can be attached to the same patch, with the results
from the sandwich assay decoded based on the 2-D array position of
the individual structures. This essentially allows array-style
processing without the need for sample extraction, purification,
labelling, etc.
[0563] Accordingly, in one example, the above described system
provides a minimally-invasive and pain-free way to access
blood-borne biomarkers of disease: by accessing the outer skin
layers with devices applied to the skin that are also pain-free.
Currently, blood is accessed by a needle/lancet which is often
painful and laborious. Alternatively, blood is accessed directly in
the body by surgically implanting a sensor. Surgical implants are
not likely to be used widely, as implanting is an invasive
procedure, with limited choice of materials suitable for
implantation.
[0564] The system can provide rapid "on the spot" disease detection
on the person, rather than the delays of sending blood samples to
pathology laboratories for processing. This is also an advance over
the current point-of-care devices, which usually still require a
blood sample (e.g. by a needle) to be analysed away from the
body.
[0565] The system can provide high-fidelity, low power, low cost
body signal (e.g. biopotential, optical) sensing for practical
disease/health diagnostics. As one example, pre-clinical animal
skin testing of microstructure patches show a 100 fold reduction of
bioimpedance, compared to standard, approaches applied to the
surface of skin, leading to improved signal to noise ratio.
[0566] The system can provide simple, semi-continuous or continuous
monitoring: a low cost-device micro wearable would be applied to
the skin and potentially be worn for days (or longer), and then
simply replaced by another micro wearable component. Thus, micro
wearables provide a route for monitoring over time--which can be
particularly important in detecting sudden events (e.g. cardiac
biomarkers for a heart attack)--without surgically implanting a
sensor into the body.
[0567] In one example, the above described approach can allow
wearables to provide widespread, low-cost healthcare monitoring for
a multitude of health conditions that cannot be assayed by current
devices, which are placed on the skin.
[0568] In one example, the microstructure patches penetrate the
skin barrier and so unlike today's wearables, access blood-borne
biomarkers of disease for rapid "on the spot" disease detection on
the person. Contrast this to the current method of sending blood
samples to pathology laboratories for processing. This is also an
advance over the current point-of-care devices, which usually still
require a blood sample (e.g. by a needle) to be analysed away from
the body.
[0569] In one example, the system can provide a low-cost
microstructure patches would be applied to the skin and potentially
be worn for days (or longer) for simple and pain free
semi-continuous or continuous monitoring, and then simply replaced
by another microstructure patch component. Thus, microstructure
patches provide a route for monitoring over time--which can be
particularly important in detecting sudden events (e.g. cardiac
biomarkers for a heart attack)--without surgically-implanting a
sensor into the body.
[0570] Embodiment 1. A system for performing measurements on a
biological subject, the system including: at least one substrate
including one or more microstructures configured to breach a
functional barrier of the subject; and, an actuator configured to
apply a force to the substrate to cause the microstructures to
breach the functional barrier.
[0571] Embodiment 2. A system according to embodiment 1, wherein
the actuator is at least one of: an electric actuator; a magnetic
actuator; a polymeric actuator; a fabric or woven actuator; a
pneumatic actuator; a thermal actuator; a hydraulic actuator; a
chemical actuator; a piezoelectric actuator; and, a mechanical
actuator.
[0572] Embodiment 3. A system according to embodiment 1 or
embodiment 2, wherein the actuator is configured to apply at least
one of: a vibratory force; a periodic force; a repeated force; a
single continuous force; and, a single instantaneous force.
[0573] Embodiment 4. A system according to embodiment 3, wherein
the force is applied at a frequency that is at least one of: at
least 0.01 Hz; at least 0.1 Hz; at least 1 Hz; at least 10 Hz; at
least 50 Hz; at least 100 Hz; at least 1 kHz; at least 10 kHz; at
least 100 kHz; varying; varying depending on at least one of: a
time of application; a depth of penetration; a degree of
penetration; and, an insertion resistance; and, increasing with an
increasing depth of penetration; decreasing with an increasing
depth of penetration; increasing until a point of penetration; and
decreasing after a point of penetration.
[0574] Embodiment 5. A system according to any one of the
embodiments 1 to 4, wherein the force is at least one of: at least
0.1 .mu.N; at least 1 .mu.N; at least 5 .mu.N; at least 10 .mu.N;
at least 20 .mu.N; at least 50 .mu.N; at least 100 .mu.N; at least
500 .mu.N; at least 1000 .mu.N; at least 10 mN; at least 100 mN;
varying depending on at least one of: a time of application; a
depth of penetration; a degree of penetration; and, an insertion
resistance; increasing with an increasing depth of penetration;
decreasing with an increasing depth of penetration; increasing
until a point of penetration; and decreasing after a point of
penetration.
[0575] Embodiment 6. A system according to any one of the
embodiments 1 to 5, wherein the actuator is configured to cause
movement of the microstructures that is at least one of: greater
than 0.001 times a length of the microstructure; greater than 0.01
times a length of the microstructure; greater than 0.1 times a
length of the microstructure; greater than a length of the
microstructure; greater than 10 times a length of the
microstructure; greater than 100 times a length of the
microstructure; and, greater than 1000 times a length of the
microstructure. varying depending on at least one of: a time of
application; a depth of penetration; a degree of penetration; and,
an insertion resistance; increasing with an increasing depth of
penetration; decreasing with an increasing depth of penetration;
increasing until a point of penetration; and decreasing after a
point of penetration.
[0576] Embodiment 7. A system according to any one of the
embodiments 1 to 6, wherein the system: detects, using response of
the actuator, at least one of: a depth of penetration; a degree of
penetration; and, an insertion resistance; controls the actuator in
accordance with the detection.
[0577] Embodiment 8. A system according to any one of the
embodiments 1 to 7, wherein the system: detects, using measured
response signals, at least one of: breaching of the barrier by the
microstructures; and, a depth of penetration by the
microstructures; controls the actuator in accordance with the
detection.
[0578] Embodiment 9. A system according to any one of the
embodiments 1 to 8, wherein the actuator is configured to at least
one of: physically disrupt a coating on the microstructures;
dislodge a coating on the microstructures; physically stimulate the
subject; cause the microstructures to penetrate the barrier;
retract the microstructures from the barrier; and, retract the
microstructures from the subject.
[0579] Embodiment 10. A system according to any one of the
embodiments 1 to 9, wherein the system includes a housing that at
least one of: contains the actuator; and, acts as the actuator.
[0580] Embodiment 11. A system according to embodiment 10, wherein
the housing selectively couples to the substrate.
[0581] Embodiment 12. A system according to embodiment 11, wherein
the housing couples to the substrate using at least one of:
mechanical coupling; adhesive coupling; and, magnetic coupling.
[0582] Embodiment 13. A system according to any one of the
embodiments 8 to 12, wherein the housing includes housing
connectors that operatively connect to substrate connectors on the
substrate to allow signals to be applied to and/or received from
the microstructures.
[0583] Embodiment 14. A system according to any one of the
embodiments 1 to 13, wherein at least one of a housing and
substrate are at least one of: secured to the subject; secured to
the subject using anchor microstructures; secured to the subject
using an adhesive patch; and, secured to the subject using a
strap.
[0584] Embodiment 15. A system according to any one of the
embodiments 1 to 14, wherein the actuator is operatively coupled to
the substrate.
[0585] Embodiment 16. A system according to any one of the
embodiments 1 to 15, wherein the system includes at least one of:
at least one sensor operatively connected to at least one
microstructure, the at least one sensor being configured to measure
response signals from the at least one microstructure; and, a
signal generator operatively connected to at least one
microstructure to apply a stimulatory signal to the at least one
microstructure.
[0586] Embodiment 17. A system according to embodiment 16, wherein
the system includes one or more electronic processing devices that
at least one of: determine measured response signals; and, control
the signal generator.
[0587] Embodiment 18. A system according to any one of the
embodiments 1 to 17, wherein the system includes one or more
electronic processing devices that control the actuator.
[0588] Embodiment 19. A system according to any one of the
embodiments 1 to 18, wherein the actuator is configured to at least
one of: physically disrupt a coating on the microstructures;
dislodge a coating on the microstructures; physically stimulate the
subject; cause the microstructures to penetrate the barrier;
retract the microstructures from the barrier; and, retract the
microstructures from the subject.
[0589] Embodiment 20. A system according to any one of the
embodiments 1 to 19, wherein the functional barrier is at least one
of: multiple layers; a mechanical discontinuity; a tissue
discontinuity; a cellular discontinuity; a neural barrier; a sensor
barrier; a cellular layer; a skin layer; a mucosal layer; an
internal barrier; an external barrier; an inner barrier within an
organ; an outer barrier of an organ; an epithelial layer; an
endothelial layer; a melanin layer; an optical barrier; an
electrical barrier; molecular weight barrier; basal layer; and, a
stratum corneum.
[0590] Embodiment 21. A system according to any one of the
embodiments 1 to 20, wherein at least one of the substrate and the
microstructures include at least one of: fabric; woven fabric;
electronic fabric; natural fibres; silk; organic materials; natural
composite materials; artificial composite materials; ceramics;
stainless steel; metal; polymer; silicon; semiconductor;
organosilicates; gold; silver; carbon; carbon nano materials;
platinum; and, titanium.
[0591] Embodiment 22. A system according to any one of the
embodiments 1 to 21, wherein the substrate and microstructures
include at least one of: the same material; and, different
materials.
[0592] Embodiment 23. A system according to any one of the
embodiments 1 to 22, wherein the substrate is at least one of: at
least partially flexible; configured to conform to an outer surface
of the functional barrier; and, configured to conform to a shape of
at least part of a subject.
[0593] Embodiment 24. A system according to any one of the
embodiments 1 to 23, wherein at least some of the microstructures
are at least one of: blades; ridges; needles; and, plates.
[0594] Embodiment 25. A system according to any one of the
embodiments 1 to 24, wherein at least some of the microstructures
at least one of: are at least partially tapered; have a cross
sectional shape that is at least one of: circular; rectangular;
cruciform; square; rounded square; rounded rectangular;
ellipsoidal; and, at least partially hollow; have a surface that is
at least partially at least one of: smooth; serrated; includes one
or more pores; includes one or more raised portions; and, rough;
are at least partially hollow; are porous; and, include an internal
structure.
[0595] Embodiment 26. A system according to any one of the
embodiments 1 to 25, wherein the microstructures include anchor
microstructures used to anchor the substrate to the subject.
[0596] Embodiment 27. A system according to embodiment 26, wherein
the anchor microstructures at least one of: undergo a shape change;
undergo a shape change in response to at least one of substances in
the subject and applied stimulation; swell; swell in response to at
least one of substances in the subject and applied stimulation;
include anchoring structures; have a length greater than that of
other microstructures; and, enter the dermis.
[0597] Embodiment 28. A system according to any one of the
embodiments 1 to 27, wherein the microstructures have a length that
is at least one of: greater than the thickness of the functional
barrier; at least 10% greater than the thickness of the functional
barrier; at least 20% greater than the thickness of the functional
barrier; at least 50% greater than the thickness of the functional
barrier; at least 75% greater than the thickness of the functional
barrier; at least 100% greater than the thickness of the functional
barrier; no more than 2000% greater than the thickness of the
functional barrier; no more than 1000% greater than the thickness
of the functional barrier; no more than 500% greater than the
thickness of the functional barrier; no more than 100% greater than
the thickness of the functional barrier; no more than 75% greater
than the thickness of the functional barrier; and, no more than 50%
greater than the thickness of the functional barrier.
[0598] Embodiment 29. A system according to any one of the
embodiments 1 to 28, wherein the microstructures are applied to
skin of the subject, and wherein at least some of the
microstructures at least one of: penetrate the stratum corneum;
enter the viable epidermis but not the dermis; and, enter the
dermis.
[0599] Embodiment 30. A system according to any one of the
embodiments 1 to 29, wherein at least some of the microstructures
have a length that is at least one of: less than 2500 .mu.m; less
than 1000 .mu.m; less than 750 .mu.m; less than 600 .mu.m; less
than 500 .mu.m; less than 400 .mu.m; less than 300 .mu.m; less than
250 .mu.m; greater than 50 .mu.m; and, greater than 100 .mu.m.
[0600] Embodiment 31. A system according to any one of the
embodiments 1 to 30, wherein at least some of the microstructures
have a maximum width that is at least one of: less than 50000
.mu.m; less than 40000 .mu.m; less than 30000 .mu.m; less than
20000 .mu.m; less than 10000 .mu.m; less than 1000 .mu.m; less than
500 .mu.m; less than 100 .mu.m; less than 50 .mu.m; less than 40
.mu.m; less than 30 .mu.m; less than 20 .mu.m; and, less than 10
.mu.m.
[0601] Embodiment 32. A system according to any one of the
embodiments 1 to 31, wherein at least some of the microstructures
have a maximum thickness that is at least one of: less than 1000
.mu.m; less than 500 .mu.m; less than 200 .mu.m; less than 100
.mu.m; less than 50 .mu.m; less than 20 .mu.m; less than 10 .mu.m;
at least 1 .mu.m; at least 0.5 .mu.m; and, at least 0.1 .mu.m.
[0602] Embodiment 33. A system according to any one of the
embodiments 1 to 32, wherein the microstructures have a density
that is at least one of: less than 50,000 per cm.sup.2; less than
30,000 per cm.sup.2; less than 10,000 per cm.sup.2; less than 1,000
per cm.sup.2; less than 500 per cm.sup.2; less than 100 per
cm.sup.2; less than 10 per cm.sup.2; and, less than 5 per
cm.sup.2.
[0603] Embodiment 34. A system according to any one of the
embodiments 1 to 33, wherein the microstructures have a spacing
that is at least one of: less than 20 mm; less than 10 mm; less
than 1 mm; less than 0.1 mm; and, less than 10 .mu.m.
[0604] Embodiment 35. A system according to any one of the
embodiments 1 to 34, wherein the microstructures include a material
including at least one of: a bioactive material; a reagent for
reacting with analytes in the subject; a binding agent for binding
with analytes of interest; a probe for selectively targeting
analytes of interest; a material to reduce biofouling; a material
to attract at least one substance to the microstructures; a
material to repel at least one substance from the microstructures;
a material to attract at least some analytes to the projections;
and, a material to repel at least some analytes from the
projections.
[0605] Embodiment 36. A system according to any one of the
embodiments 1 to 35, wherein the substrate includes a plurality of
microstructures and wherein different microstructures are at least
one of: differentially responsive to analytes; responsive to
different analytes; responsive to different combination of
analytes; and, responsive to different concentrations of
analytes.
[0606] Embodiment 37. A system according to any one of the
embodiments 1 to 36, wherein at least some of the microstructures
at least one of: attracts at least one substance to the
microstructures; repels at least one substance from the
microstructures; attracts at least one analyte to the
microstructures; and, repels at least one analyte from the
microstructures.
[0607] Embodiment 38. A system according to any one of the
embodiments 1 to 37, wherein the microstructures are configured to
deliver stimulation including at least one of: chemical
stimulation; mechanical stimulation; magnetic stimulation; thermal
stimulation; electrical stimulation; electromagnetic stimulation;
optical stimulation; and, stimulation to trigger a biological
response in the subject.
[0608] Embodiment 39. A system according to any one of the
embodiments 1 to 38, wherein the one or more microstructure
electrodes interact with one or more analytes of interest such that
a response signal is dependent on a presence, absence, level or
concentration of analytes of interest.
[0609] Embodiment 40. A system according to any one of the
embodiments 1 to 39, wherein at least some of the microstructures
are coated with a coating.
[0610] Embodiment 41. A system according to embodiment 40, wherein
at least one of: at least some microstructures are uncoated; at
least some microstructures are porous with an internal coating; at
least some microstructures are partially coated; different
microstructures have different coatings; different parts of
microstructures include different coatings; and, at least some
microstructures include multiple coatings.
[0611] Embodiment 42. A system according to embodiment 40 or
embodiment 41, wherein stimulation is used to at least one of:
release material from the coating on the microstructure; disrupt
the coating; dissolve the coating; and, release the coating.
[0612] Embodiment 43. A system according to any one of the
embodiments 40 to 42, wherein at least some of the microstructures
are coated with a selectively dissolvable coating.
[0613] Embodiment 44. A system according to embodiment 43, wherein
the selectively dissolvable coating dissolves at least one of:
after a defined time period; in response to application of a
stimulatory signal; in response to a presence, absence, level or
concentration of analytes; and, upon breaching or penetration of
the functional barrier.
[0614] Embodiment 45. A system according to embodiment 44, wherein
the system is configured to: detect the coating dissolving; and,
perform at least one measurement after the coating has
dissolved.
[0615] Embodiment 46. A system according to embodiment 45, wherein
the system is configured to detect the coating dissolving based on
a change in a response signal.
[0616] Embodiment 47. A system according to any one of the
embodiments 40 to 46, wherein the coating at least one of:
undergoes a shape change to selectively anchor microstructures;
modifies surface properties to at least one of: increase
hydrophilicity; increase hydrophobicity; minimize biofouling;
attracts at least one substance to the microstructures; repels at
least one substance from the microstructures; provides a physical
structure to at least one of: facilitate penetration of the
barrier; strengthen the microstructures; and, anchor the
microstructures in the subject; dissolves to at least one of:
expose a microstructure; expose a further coating; and, expose a
material; provides stimulation to the subject; contains a material;
and, selectively releases a material.
[0617] Embodiment 48. A system according to any one of the
embodiments 1 to 47, wherein the microstructures are configured to
deliver stimulation to trigger a biological response in the
subject.
[0618] Embodiment 49. A system according to any one of the
embodiments 1 to 48, wherein the system is configured to perform
repeated measurements over a time period.
[0619] Embodiment 50. A system according to embodiment 49, wherein
the time period is at least one of: less than 0.01 seconds; less
than 0.1 seconds; less than 1 second; less than 10 seconds; at
least one hour; at least one day; and, at least one week.
[0620] Embodiment 51. A system according to embodiment 49 or
embodiment 50, wherein the microstructures are configured to remain
in the subject during the time period.
[0621] Embodiment 52. A system according to embodiment 49 or
embodiment 50, wherein the microstructures are configured to be
removed when measurements are not being performed.
[0622] Embodiment 53. A system according to any one of the
embodiments 1 to 52, wherein the actuator is configured to apply a
force to the substrate to at least one of: sense tissue mechanical
properties; provide mechanical stimulation; attract or repel
substances; trigger a biological response; release material from a
coating on at least some microstructures; disrupt a coating on at
least some microstructures; dissolve a coating on at least some
microstructures; dislodge a coating on the microstructures; release
a coating on at least some microstructures. cause the
microstructures to penetrate the barrier; retract the
microstructures from the barrier; and, retract the microstructures
from the subject.
[0623] Embodiment 54. A system according to any one of the
embodiments 1 to 53, wherein the system is at least partially
wearable.
[0624] Embodiment 55. An actuator configured to apply a force to a
substrate to cause one or more microstructures provided on the
substrate to penetrate a functional barrier of a biological
subject.
[0625] Embodiment 56. A method for performing measurements on a
biological subject, the method including: using at least one
substrate including one or more microstructures to breach a
functional barrier of the subject; and, using an actuator
configured to apply a force to the substrate to cause the
microstructures to breach the functional barrier.
[0626] Persons skilled in the art will appreciate that numerous
variations and modifications will become apparent. All such
variations and modifications which become apparent to persons
skilled in the art, should be considered to fall within the spirit
and scope that the invention broadly appearing before
described.
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